Benzenesulfonamide compounds and the use thereof

ABSTRACT

The invention relates to azetidinyl, pyrrolidinyl, piperidinyl, and hexahydroazepinyl compounds of Formula (I): and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein R 1 , R 2 , R 3 , Z and q are defined as set forth in the specification. The invention is also directed to the use compounds of Formula I to treat a disorder responsive to the blockade of calcium channels, and particularly N-type calcium channels. Compounds of the present invention are especially useful for treating pain.

This application is a National Stage of International Application No.PCT/IB2008/002575, filed Sep. 26, 2008, which claims the benefit of U.S.Provisional Application No. 60/960,406, filed Sep. 28, 2007.

BACKGROUND OF THE INVENTION Field of the Invention

This invention is in the field of medicinal chemistry. The inventionrelates to novel azetidinyl, pyrrolidinyl, piperidinyl, andhexahydroazepinyl compounds and the use of these compounds as blockersof calcium (Ca²⁺) channels.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

The content of the electronically submitted Sequence Listing (Name:1861_(—)2320002_SequenceListing_ascii.txt; Size: 2,634 bytes; and Dateof Creation: Feb. 19, 2013) filed herewith is incorporated herein byreference in its entirety.

BACKGROUND ART

Calcium ions play fundamental roles in the regulation of many cellularprocesses. It is therefore essential that their intracellular levels bemaintained under strict, yet dynamic control (Davila, H. M., Annals ofthe New York Academy of Sciences, pp. 102-117 (1999)). Voltage-gatedcalcium channels (VGCC) serve as one of the important mechanisms forfast calcium influx into the cell. Calcium channels arehetero-oligomeric proteins consisting of a pore-forming subunit (α1),which is able to form functional channels on its own in heterologousexpression systems, and a set of auxiliary or regulatory subunits.Calcium channels have been classified based on their pharmacologicaland/or electrophysiological properties. The classification ofvoltage-gated calcium channels divides them into three groups: (i) highvoltage-activated (HVA) channels, which include L-, N-, P-, and Q-types;(ii) intermediate (IVA) voltage-activated R-type channels; and (iii) lowvoltage-activated (LVA) T-type channels (Davila, supra). Voltage-gatedcalcium channels (VGCC) are also known as voltage-dependent calciumchannels (VDCC) or voltage-sensitive calcium channels (VSCC).

Voltage-sensitive calcium channels (VSCC) regulate intracellular calciumconcentration, which affects various important neuronal functions suchas cellular excitability, neurotransmitter release, hormone secretion,intracellular metabolism, neurosecretory activity and gene expression(Hu et al., Bioorganic & Medicinal Chemistry 8:1203-1212 (2000)). N-typechannels are found mainly in central and peripheral neurons, beingprimarily located on presynaptic nerve terminals. These channelsregulate the calcium flux required for depolarization-evoked release ofa transmitter from synaptic endings. The transmission of pain signalsfrom the periphery to the central nervous system (CNS) is mediated byN-type calcium channels located in the spinal cord (Song et al., J. Med.Chem. 43:3474-3477 (2000)).

The six types of calcium channels (i.e., L, N, P, Q, R, and T) areexpressed throughout the nervous system (Wallace, M. S., The ClinicalJournal of Pain 16:580-585 (2000)). Voltage-sensitive calcium channelsof the N-type exist in the superficial laminae of the dorsal horn andare thought to modulate nociceptive processing by a central mechanism.Blockade of the N-type calcium channel in the superficial dorsal hornmodulates membrane excitability and inhibits neurotransmitter release,resulting in pain relief. Wallace (supra) suggests that based on animalmodels, N-type calcium channel antagonists have a greater analgesicpotency than sodium channel antagonists.

N-type calcium channel blockers have usefulness for neuroprotection andanalgesia. Ziconotide, which is a selective N-type calcium channelblocker, has been found to have analgesic activity in animal models andneuroprotective activity in focal and global ischemia models (Song etal., supra). Examples of known calcium channel blockers includeflunarizine, fluspirilene, cilnipide, PD 157767, SB-201823, SB-206284,NNC09-0026, and PD 151307 (Hu et al., supra).

Blockade of N-type channels can prevent and/or attenuate subjective painas well as primary and/or secondary hyperalgesia and allodynia in avariety of experimental and clinical conditions (Vanegas, H. et al.,Pain 85:9-18 (2000)). N-type voltage-gated calcium channels (VGCC) playa major role in the release of synaptic mediators such as glutamate,acetylcholine, dopamine, norepinephrine, gamma-aminobutyric acid (GABA)and calcitonin gene-related peptide (CGRP).

Inhibition of voltage-gated L-type calcium channels has been shown to bebeneficial for neuroprotection (Song et al., supra). However, inhibitionof cardiac L-type calcium channels can lead to hypotension. It isbelieved that a rapid and profound lowering of arterial pressure tendsto counteract the neuroprotective effects of L-type calcium channelblockers. A need exists for antagonists that are selective for N-typecalcium channels over L-type calcium channels to avoid potentialhypotensive effects.

BRIEF SUMMARY OF THE INVENTION

The present invention is related to the use of azetidinyl, pyrrolidinyl,piperidinyl, and hexahydroazepinyl benzenesulfonamides represented byFormula I, below, and the pharmaceutically acceptable salts, prodrugsand solvates thereof, as blockers of calcium (Ca²⁺) channels. Compoundsof Formula I show selectivity as N-type calcium channel blockers.

The invention is also related to treating a disorder responsive to theblockade of calcium channels in a mammal suffering from excess activityof said channels by administering an effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt, prodrug or solvatethereof, as described herein. Specifically, the invention is related totreating a disorder responsive to the blockade of N-type calciumchannels in a mammal suffering from excess activity of said channels byadministering an effective amount of a compound of Formula I, or apharmaceutically acceptable salt, prodrug or solvate thereof, asdescribed herein.

Compounds useful in the present invention have not been heretoforereported. Thus, one aspect of the present invention is directed to novelcompounds of Formula I, as well as their pharmaceutically acceptablesalts, prodrugs and solvates.

Another aspect of the present invention is directed to the use of thenovel compounds of Formula I, and their pharmaceutically acceptablesalts, prodrugs and solvates, as blockers of N-type calcium channels.

A further aspect of the present invention is to provide a method fortreating pain (e.g., acute pain, chronic pain, which includes but is notlimited to, neuropathic pain and inflammatory pain, or surgical pain) byadministering an effective amount of a compound of Formula I, or apharmaceutically acceptable salt, prodrug or solvate thereof, to amammal in need of such treatment. Specifically, the present inventionprovides a method for preemptive or palliative treatment of pain byadministering an effective amount of a compound of Formula I, or apharmaceutically acceptable salt, prodrug or solvate thereof, to amammal in need of such treatment.

A further aspect of the present invention is to provide a method fortreating stroke, neuronal damage resulting from head trauma, epilepsy,migraine, a mood disorder, schizophrenia, a neurodegenerative disorder(e.g., Alzheimer's disease, amyotrophic lateral sclerosis (ALS), orParkinson's disease), depression, anxiety, a psychosis, hypertension, orcardiac arrhythmia, by administering an effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt, prodrug or solvatethereof, to a mammal in need of such treatment.

A further aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating a disorder responsive to the blockade ofcalcium ion channels, especially N-type calcium ion channels, saidpharmaceutical composition containing an effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt, prodrug or solvatethereof, in a mixture with one or more pharmaceutically acceptablecarriers.

Also, an aspect of the invention is to provide a method of modulatingcalcium channels, especially N-type calcium channels, in a mammal,wherein said method comprises administering to the mammal an effectiveamount of at least one compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof.

A further aspect of the present invention is to provide radiolabeledcompounds of Formula I and the use of such compounds, or theirpharmaceutically acceptable salts, prodrugs or solvates, as radioligandsfor their binding site on the calcium channel.

A further aspect of the invention is to provide a method for screening acandidate compound for the ability to bind to a receptor using aradiolabeled compound of Formula I, which includes but is not limitedto, a ³H, ¹¹C, and ¹⁴C radiolabeled compound of Formula I, or apharmaceutically acceptable salt, prodrug or solvate thereof. Thismethod comprises a) introducing a fixed concentration of theradiolabeled compound to the receptor to form a mixture; b) titratingthe mixture with a candidate compound; and c) determining the binding ofthe candidate compound to said receptor.

A further aspect of the invention is to provide the use of a compound ofFormula I, or a pharmaceutically acceptable salt, prodrug or solvatethereof, in the manufacture of a medicament for treating pain in amammal. In one embodiment, the invention provides the use of a compoundof Formula I, or a pharmaceutically acceptable salt, prodrug or solvatethereof, in the manufacture of a medicament for palliative or preemptivetreatment of pain, such as acute pain, chronic pain, or surgical pain.

A further aspect of the invention is to provide the use of a compound ofFormula I, or a pharmaceutically acceptable salt, prodrug or solvatethereof, in the manufacture of a medicament for treating stroke,neuronal damage resulting from head trauma, epilepsy, migraine, a mooddisorder, schizophrenia, a neurodegenerative disorder, depression,anxiety, a psychosis, hypertension, or cardiac arrhythmia in a mammal.

Additional embodiments and advantages of the invention will be set forthin part in the description that follows, and will flow from thedescription, or may be learned by practice of the invention. Theembodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only and are notrestrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention is based on the use of compounds ofFormula I, and the pharmaceutically acceptable salts, prodrugs andsolvates thereof, as blockers of Ca²⁺ channels. In view of thisproperty, compounds of Formula I, and the pharmaceutically acceptablesalts, prodrugs and solvates thereof, are useful for treating disordersresponsive to the blockade of calcium ion channels. In one aspect,compounds of Formula I, and the pharmaceutically acceptable salts,prodrugs and solvates thereof, selectively block N-type calcium ionchannels and, thus, are useful for treating disorders responsive to theselective blockade of N-type calcium ion channels.

The compounds useful in this aspect of the invention are compoundsrepresented by Formula I:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein:

R¹ and R² are each independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, halogen, alkoxy, haloalkoxy, cyano, nitro,amino, aminoalkyl, alkylamino, dialkylamino, hydroxy, carboxy,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, anddialkylaminocarbonyl;

R³ is selected from the group consisting of alkyl, alkenyl, cycloalkyl,cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl, 3-tetrahydrofuranylalkyl,alkylsulfonylaminoalkyl, aminocarbonylalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, cyanoalkyl, carboxyalkyl, andalkoxycarbonylalkyl;

p is 1 or 2;

q is 0, 1, 2, or 3;

Z is selected from the group consisting of Z¹, Z², Z³, Z⁴, an Z⁵, a Lwherein:

-   Z¹ is    —(CH₂)_(m)—NH—C(O)—R⁴;-   Z² is    —CR⁵R⁶—(CH₂)_(n)—C(O)—O—R⁷;-   Z³ is    —CR⁸R⁹—(CH₂)_(r)—R¹⁰;-   Z⁴ is    —CR¹¹R¹²—(CH₂)_(s)—C(O)—NR¹³R¹⁴; and-   Z⁵ is aryl or heteroaryl substituted with at least one of    alkoxycarbonyl, haloalkyl, carboxy, aminocarbonyl,    alkylaminocarbonyl, or dialkylaminocarbonyl, wherein said aryl or    heteroaryl can be further optionally substituted;

R⁴ is selected from the group consisting of

-   -   alkyl;    -   phenyl optionally substituted with one or more substituents each        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,        cyano, amino, aminoalkyl, alkylamino, dialkylamino, and        hydroxyalkylamino;    -   heteroaryl optionally substituted with one or more substituents        each independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,        cyano, amino, aminoalkyl, alkylamino, dialkylamino, and        hydroxyalkylamino; and    -   —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are each independently        selected from the group consisting of hydrogen, alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl, provided that when R^(4b) is optionally substituted        heteroaryl, then R^(4a) is alkyl, optionally substituted aryl,        or optionally substituted heteroaryl;

R⁵ and R⁶ are each independently hydrogen, alkyl, alkoxy, or phenyloptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,and dialkylamino;

R⁷ is selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,alkoxyalkyl, cyanoalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted heteroaryl, and optionallysubstituted heteroarylalkyl; provided that when R⁷ is alkyl, then atleast one of R⁵ or R⁶ is other than hydrogen;

R⁸ and R⁹ are both hydrogen or together form ═O; provided that when R⁸and R⁹ together form ═O, then r is other than 0 (zero);

R¹⁰ is a 5-membered, N-containing heteroaryl or a 5-membered, partiallyunsaturated, N-containing heterocyclo each of which is optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,and dialkylamino;

R¹¹, R¹² and R¹³ are each independently hydrogen, alkyl or phenyloptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,and dialkylamino; and

R¹⁴ is alkyl, mono-, bi- or tricycloalkyl, optionally substitutedheterocyclo, or optionally substituted aryl; provided that when R¹⁴ isalkyl or optionally substituted aryl, then at least one of R¹¹ or R¹² isother than hydrogen; or

R¹¹ is hydrogen, R¹² and R¹³ together form a bridge —CH₂—CH₂— or—CH₂—CH₂—CH₂—, and R¹⁴ is hydrogen, alkyl, monocycloalkyl, bicycloalkyl,tricycloalkyl, optionally substituted heterocyclo, or optionallysubstituted aryl; or

R¹¹ and R¹² are both hydrogen and R¹³ and R¹⁴ together with the nitrogenatom to which they are attached form a 4- to 7-membered heterocyclicring;

m is 1, 2, or 3;

n is 0, 1, 2, or 3;

r is 0, 1, 2, or 3; and

s is 0, 1, or 2.

The carbon of the azetidinyl, pyrrolidinyl, piperidinyl, andhexahydroazepinyl ring where the Z group is attached, can be a chiralcenter. Accordingly, the configuration at those carbon atoms can be (R)or (S).

In one embodiment, compounds useful in the present invention arecompounds represented by Formula II:

and pharmaceutically acceptable salts, prodrugs, and solvates thereof,wherein R¹, R², p, q, and Z are as defined above.

In one embodiment, compounds useful in the present invention arecompounds represented by Formula III:

and pharmaceutically acceptable salts, prodrugs, and solvates thereof,wherein R¹, R², p, q, and Z are as defined above.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III where q is 0 and p is 1 (azetidinyl).

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III where q is 1 and p is 1(pyrrolidinyl).

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III where q is 2 and p is 1(3-piperidinyl).

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III where q is 1 and p is 2(4-piperidinyl).

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III where q is 3 and p is 1(3-hexahydroazepinyl).

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III where q is 2 and p is 2(4-hexahydroazepinyl).

The groups R¹ and R², when they are not equal to H, each take the placeof a hydrogen atom that would otherwise be present in any position onthe phenyl ring to which the particular R group is attached. Similarly,optional substituents attached to aryl, phenyl, and heteroaryl ringseach take the place of a hydrogen atom that would otherwise be presentin any position on the aryl or heteroaryl rings.

Preferably, in compounds of Formulae I and II, R¹ and R² are eachindependently selected from the group consisting of hydrogen, halogen,alkyl, haloalkyl, cyano, alkoxy, haloalkoxy, nitro, amino, alkylamino,and dialkylamino. More preferably, R¹ and R² are each independentlyselected from the group consisting of hydrogen, halogen, C₁₋₆ alkyl,halo(C₁₋₆)alkyl, cyano, C₁₋₆ alkoxy, halo(C₁₋₆)alkoxy, nitro, amino,C₁₋₆ alkylamino, and di(C₁₋₆)alkylamino; and more preferablyindependently selected from the group consisting of hydrogen, halogen,C₁₋₃ alkyl, halo(C₁₋₃)alkyl, cyano, C₁₋₃ alkoxy, halo(C₁₋₃)alkoxy, andnitro. Advantageously, R¹ and R² are independently hydrogen, methyl,ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, fluoromethyl,cyano, nitro, methoxy or difluoromethoxy. More preferably, R¹ ishydrogen and R² is trifluoromethyl, or both R¹ and R² are hydrogen.Preferably, R² is in the meta-position of the phenyl ring.

Preferably, R³ is selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl, alkylsulfonylaminoalkyland aminocarbonylalkyl; more preferably selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₃ alkoxy(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,3-tetrahydrofuranyl, 2-tetrahydrofuranyl(C₁₋₃)alkyl, C₃₋₆cycloalkyl(C₁₋₃)alkyl, C₁₋₃ alkylsulfonylamino(C₁₋₃)alkyl, andaminocarbonyl(C₁₋₃)alkyl. Advantageously, R³ is selected from the groupconsisting of methyl, ethyl, iso-pentyl, iso-butyl, iso-propyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl,cyclopropylethyl, methoxymethyl, methoxyethyl, hydroxymethyl,hydroxyethyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,2-tetrahydrofuranylethyl, methylsulfonamidomethyl,methylsulfonamidoethyl, aminocarbonylmethyl, and aminocarbonylethyl.More advantageously, R³ is cyclopropyl, methyl, isopropyl, or isobutyl,especially cyclopropyl or isopropyl.

Preferably, in compounds of Formulae I and II, R¹ and R² are eachindependently selected from the group consisting of hydrogen, halogen,alkyl, haloalkyl, cyano, alkoxy, haloalkoxy, amino, alkylamino,dialkylamino, and nitro; and R³ is selected from the group consisting ofmethyl, ethyl, iso-pentyl, iso-butyl, iso-propyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclopropylethyl,methoxymethyl, methoxyethyl, hydroxymethyl, hydroxyethyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,2-tetrahydrofuranylethyl, methylsulfonamidomethyl,methylsulfonamidoethyl, aminocarbonylmethyl, and aminocarbonylethyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z¹. In one embodiment,compounds useful in the present invention are compounds of any ofFormulae I-III, wherein R⁴ is alkyl. In another embodiment, compoundsuseful in the present invention are compounds of any of Formulae I-III,wherein R⁴ is phenyl or heteroaryl, each of which is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,dialkylamino, and hydroxyalkylamino. Useful compounds of the presentinvention include those where R⁴ is phenyl substituted with one, two orthree substituents, preferably one or two substituents, eachindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino,aminoalkyl, alkylamino, dialkylamino, and hydroxyalkylamino; preferablyeach independently selected from the group consisting of C₁₋₆ alkyl,C₁₋₆ alkoxy, halogen, halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy,hydroxy(C₁₋₆)alkyl, cyano, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, and hydroxy(C₁₋₆)alkylamino; more preferably eachindependently selected from the group consisting of C₁₋₃ alkyl, halogen,and halo(C₁₋₃)alkyl; and especially each independently selected from thegroup consisting of methyl, fluoro and trifluoromethyl.

Useful compounds of the present invention include also those where R⁴ isheteroaryl selected from the group consisting of pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazinyl, pyrrolyl and pyrazolyl, all of whichcan be optionally substituted with one, two or three substituents,preferably one or two substituents, each independently selected from thegroup consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,dialkylamino, and hydroxyalkylamino; preferably each independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl, cyano,amino, amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, andhydroxy(C₁₋₆)alkylamino; more preferably each independently selectedfrom the group consisting of C₁₋₃ alkyl, halogen, and halo(C₁₋₃)alkyl;and especially each independently selected from the group consisting ofmethyl, fluoro and trifluoromethyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z¹ and R⁴ is—NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are each independentlyselected from the group consisting of hydrogen, alkyl, aryl, andheteroaryl, wherein said aryl or heteroaryl is optionally substitutedwith one or more substituents, preferably one or two substituents, eachindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino,aminoalkyl, alkylamino, dialkylamino, and hydroxyalkylamino; preferablyeach independently selected from the group consisting of C₁₋₆ alkyl,C₁₋₆ alkoxy, halogen, halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy,hydroxy(C₁₋₆)alkyl, cyano, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, and hydroxy(C₁₋₆)alkylamino; more preferably eachindependently selected from the group consisting of C₁₋₃ alkyl, halogen,and halo(C₁₋₃)alkyl; and especially each independently selected from thegroup consisting of methyl, fluoro and trifluoromethyl. Useful compoundsinclude those where R^(4a) and R^(4b) are each independently hydrogen orC₁₋₄ alkyl. Further useful compounds of the present invention includethose where R^(4a) is hydrogen or C₁₋₄ alkyl and R^(4b) is optionallysubstituted aryl, preferably optionally substituted phenyl. Furtheruseful compounds of the present invention include those where R^(4a) isC₁₋₄ alkyl or optionally substituted phenyl, and R^(4b) is optionallysubstituted heteroaryl, preferably optionally substituted pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl or pyrazolyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z¹ and m is 2.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z². In one embodiment,compounds useful in the present invention are compounds of any ofFormulae I-III, wherein R⁷ is hydrogen, alkyl, hydroxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl or cyanoalkyl, with theproviso that when R⁷ is alkyl, then at least one of R⁵ or R⁶ is otherthan hydrogen. Preferably, R⁷ is hydrogen, C₁₋₆ alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, C₁₋₆ alkylamino(C₁₋₆)alkyl,di(C₁₋₆)alkylamino(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl or cyano(C₁₋₆)alkyl;more preferably hydrogen, C₁₋₄ alkyl, hydroxy(C₁₋₄)alkyl,amino(C₁₋₄)alkyl, C₁₋₂ alkylamino(C₁₋₄)alkyl,di(C₁₋₂)alkylamino(C₁₋₄)alkyl, alkoxy(C₁₋₄)alkyl or cyano(C₁₋₄)alkyl;and more preferably methyl, ethyl, propyl, isopropyl, butyl ortert-butyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein R⁷ is optionally substitutedaryl, optionally substituted arylalkyl, optionally substitutedheteroaryl, or optionally substituted heteroarylalkyl; preferablyoptionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀aryl(C₁₋₄)alkyl, optionally substituted heteroaryl having 5-10 ringatoms, or optionally substituted heteroaryl(C₁₋₄)alkyl having 5-10 ringatoms; and more preferably phenyl, naphthyl, indenyl, isoindenyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, orpyrazolyl any of which can be optionally substituted. Useful compoundsare compounds of any of Formulae I-III where R⁷ is phenyl, naphthyl,indenyl, isoindenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, pyrrolyl, or pyrazolyl any of which is unsubstituted orsubstituted with one, two or three substituents, preferably one or twosubstituents, each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, dialkylamino, andhydroxyalkylamino; preferably each independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, halo(C₁₋₆)alkyl,halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl, cyano, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, andhydroxy(C₁₋₆)alkylamino; more preferably each independently selectedfrom the group consisting of C₁₋₃ alkyl, halogen, and halo(C₁₋₃)alkyl;and especially each independently selected from the group consisting ofmethyl, fluoro and trifluoromethyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z² and R⁷ isunsubstituted phenyl or phenyl substituted with one, two or threesubstituents, preferably one or two substituents, each independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,dialkylamino, and hydroxyalkylamino; preferably each independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl, cyano,amino, amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, andhydroxy(C₁₋₆)alkylamino; more preferably each independently selectedfrom the group consisting of C₁₋₃ alkyl, halogen, and halo(C₁₋₃)alkyl;and especially each independently selected from the group consisting ofmethyl, fluoro and trifluoromethyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z² and R⁵ and R⁶ areeach independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, unsubstitutedphenyl, or phenyl substituted with one or two substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,halo(C₁₋₆)alkyl, halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl, cyano,amino, amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, and di(C₁₋₆)alkylamino;preferably hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, unsubstituted phenyl, orphenyl substituted with one or two substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen,halo(C₁₋₄)alkyl, halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl, cyano,amino, amino(C₁₋₄)alkyl, C₁₋₂ alkylamino, and di(C₁₋₂)alkylamino; andmore preferably hydrogen or C₁₋₄ alkyl. Advantageously, n is 0 or 1.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z², R⁷ is selected fromthe group consisting of methyl, ethyl, propyl, isopropyl, butyl andtert-butyl. In a further aspect of said embodiment, R⁵ is C₁₋₄ alkyl,and/or R⁶ is hydrogen or C₁₋₄ alkyl, and more preferably R⁵ is C₁₋₄alkyl, and R⁶ is hydrogen or C₁₋₄ alkyl. In a preferred aspect of saidembodiment, R⁷ is selected from the group consisting of methyl, ethyl,propyl, isopropyl, butyl and tert-butyl, R⁵ is C₁₋₄ alkyl, and/or R⁶ ishydrogen or C₁₋₄ alkyl, and more preferably R⁵ is C₁₋₄ alkyl, and R⁶ ishydrogen or C₁₋₄ alkyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z³. In one embodiment,useful compounds include those where R⁸ and R⁹ are both hydrogen. In oneaspect of said embodiment, when R⁸ and R⁹ are both hydrogen and R¹⁰ isan N-containing heteroaryl, then said heteroaryl is substituted with oneor two substituents as defined above. In another embodiment, usefulcompounds include those where R⁸ and R⁹ together form ═O. In one aspectof said embodiment, when R⁸ and R⁹ together form ═O and r is not 0, thenR¹⁰ is attached by a carbon atom. In another aspect of said embodiment,when R⁸ and R⁹ together form ═O, then R³ is not cyclopropyl and/or p andq are not at the same time p=2 and q=1.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein R¹⁰ is selected from thegroup consisting of oxazolyl (oxazol-2-yl, oxazol-4-yl, or oxazol-5-yl);1,2,4-oxadiazolyl (1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl);1,3,4-oxadiazolyl (1,3,4-oxadiazol-2-yl or 1,3,4-oxadiazol-5-yl), andthiazolyl (thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl), any of which isoptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,and dialkylamino; preferably independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, halo(C₁₋₆)alkyl,halo(C₁₋₆)alkoxy, hydroxy, hydroxy(C₁₋₆)alkyl, cyano, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, and di(C₁₋₆)alkylamino; more preferablyindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, halogen, halo(C₁₋₄)alkyl, halo(C₁₋₆)alkoxy, hydroxy,hydroxy(C₁₋₄)alkyl, cyano, amino, amino(C₁₋₄)alkyl, C₁₋₂ alkylamino, anddi(C₁₋₂)alkylamino.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein R¹⁰ is selected from thegroup consisting of

wherein R¹⁰¹ is selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino,aminoalkyl, alkylamino, and dialkylamino; preferably selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, cyano, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, and di(C₁₋₆)alkylamino; morepreferably selected from the group consisting of hydrogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, halogen, halo(C₁₋₄)alkyl, hydroxy, hydroxy(C₁₋₄)alkyl,cyano, amino, amino(C₁₋₄)alkyl, C₁₋₂ alkylamino, and di(C₁₋₂)alkylamino;and A is O or S. Preferably, q is 2 and p is 1 or q is 1 and p is 2,more preferably q is 1 and p is 2. Especially, when R¹⁰ is

preferred compounds include those where q is 1 and p is 2.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z⁴. In one embodiment,compounds useful in the present invention are compounds of any ofFormulae I-III, wherein

R¹¹, R¹² and R¹³ are each independently hydrogen, alkyl or phenyloptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,and dialkylamino; and

R¹⁴ is alkyl, mono-, bi- or tricycloalkyl, optionally substitutedheterocyclo, or optionally substituted aryl; provided that when R¹⁴ isalkyl or optionally substituted aryl, then at least one of R¹¹ or R¹² isother than hydrogen.

In one embodiment, useful compounds of the present invention includethose where R¹¹ and R¹² are hydrogen or C₁₋₄ alkyl, R¹³ is hydrogen, andR¹⁴ is alkyl, mono-, bi- or tricycloalkyl, optionally substitutedheterocyclo, or optionally substituted aryl; provided that when R¹⁴ isalkyl or optionally substituted aryl, then at least one of R¹¹ or R¹² isother than hydrogen. Preferably, R¹⁴ is C₁₋₄ alkyl; C₃₋₇ monocycloalkyl;C₇₋₁₀ bicycloalkyl; C₇₋₁₂ tricycloalkyl; unsubstituted heterocyclo;heterocyclo substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, alkoxycarbonyl,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino,aminoalkyl, alkylamino, and dialkylamino; unsubstituted phenyl; orphenyl substituted with one or two substituents independently selectedfrom the group consisting of alkyl, alkoxy, alkoxycarbonyl, halogen,haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl,alkylamino, and dialkylamino. In one embodiment, useful compounds of thepresent invention include those where R¹¹, R¹², and R¹³ are eachhydrogen and R¹⁴ is mono-, bi- or tricycloalkyl, or optionallysubstituted heterocyclo. Preferable values for R¹⁴ are those definedabove.

Useful compounds of the present invention include those where R¹¹ andR¹² are hydrogen or C₁₋₄ alkyl, R¹³ is hydrogen, and R¹⁴ is methyl;ethyl; propyl; isopropyl; butyl; tert-butyl; cyclopentyl; cyclohexyl;cycloheptyl; norbornyl; optionally substituted 2- or3-tetrahydrofuranyl; optionally substituted 2- or 3-pyrrolidinyl;optionally substituted 2-, 3-, or 4-tetrahydropyranyl; optionallysubstituted 2-, 3-, or 4-piperidinyl; optionally substitutedbenzo[1,3]dioxol-5-yl; optionally substituted benzo[1,3]dioxol-4-yl; oroptionally substituted phenyl, wherein the optional substituents includeone or more, preferably one or two, groups independently selected fromthe group consisting of alkyl, alkoxy, alkoxycarbonyl, halogen,haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl,alkylamino, and dialkylamino; preferably independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl,halogen, halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, cyano, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, and di(C₁₋₆)alkylamino; morepreferably independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, halogen, halo(C₁₋₄)alkyl,hydroxy, hydroxy(C₁₋₄)alkyl, cyano, amino, amino(C₁₋₄)alkyl, C₁₋₂alkylamino, and di(C₁₋₂)alkylamino; and advantageously selected from thegroup consisting of methyl, ethyl, propyl, isopropyl, tert-butyl,methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, fluorine, chlorine,bromine, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxymethyl,cyano, amino, aminomethyl, methylamino, and dimethylamino.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein R¹¹ is hydrogen, R¹² and R¹³together form a bridge —CH₂—CH₂— or —CH₂—CH₂—CH₂—, and R¹⁴ is hydrogen,alkyl, monocycloalkyl, bicycloalkyl, tricycloalkyl, optionallysubstituted heterocyclo, or optionally substituted aryl. Usefulcompounds of the present invention include those where R¹⁴ is hydrogen,C₁₋₄ alkyl, C₃₋₇ monocycloalkyl; C₇₋₁₀ bicycloalkyl; C₇₋₁₂tricycloalkyl; unsubstituted heterocyclo; heterocyclo substituted withone or two substituents independently selected from the group consistingof alkyl, alkoxy, alkoxycarbonyl, halogen, haloalkyl, haloalkoxy,hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, anddialkylamino; unsubstituted phenyl; or phenyl substituted with one ortwo substituents independently selected from the group consisting ofalkyl, alkoxy, alkoxycarbonyl, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino.Useful compounds of the present invention include those where R¹⁴ ismethyl; ethyl; propyl; isopropyl; butyl; tert-butyl; cyclopentyl;cyclohexyl; cycloheptyl; norbornyl; optionally substituted 2- or3-tetrahydrofuranyl; optionally substituted 2- or 3-pyrrolidinyl;optionally substituted 2-, 3-, or 4-tetrahydropyranyl; optionallysubstituted 2-, 3-, or 4-piperidinyl; or optionally substituted phenyl,wherein the optional substituents include one or more, preferably one ortwo, groups independently selected from the group consisting of alkyl,alkoxy, alkoxycarbonyl, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;preferably selected from the group consisting of C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkoxycarbonyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, cyano, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, anddi(C₁₋₆)alkylamino; more preferably selected from the group consistingof C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, halogen,halo(C₁₋₄)alkyl, hydroxy, hydroxy(C₁₋₄)alkyl, cyano, amino,amino(C₁₋₄)alkyl, C₁₋₂ alkylamino, and di(C₁₋₂)alkylamino; andadvantageously selected from the group consisting of methyl, ethyl,propyl, isopropyl, tert-butyl, methoxy, ethoxy, methoxycarbonyl,ethoxycarbonyl, fluorine, chlorine, bromine, trifluoromethyl,trifluoromethoxy, hydroxy, hydroxymethyl, cyano, amino, aminomethyl,methylamino, and dimethylamino.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein R¹¹ is hydrogen, R¹² and R¹³together form a bridge —CH₂—CH₂— or —CH₂—CH₂—CH₂—, and R¹⁴ is optionallysubstituted phenyl. Preferably, R¹⁴ is unsubstituted phenyl or phenylsubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkoxy, alkoxycarbonyl, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,and dialkylamino; preferably independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, halogen,halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, cyano, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, and di(C₁₋₆)alkylamino; morepreferably independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, halogen, halo(C₁₋₄)alkyl,hydroxy, hydroxy(C₁₋₄)alkyl, cyano, amino, amino(C₁₋₄)alkyl, C₁₋₂alkylamino, and di(C₁₋₂)alkylamino; more preferably independentlyselected from the group consisting of methyl, ethyl, propyl, isopropyl,tert-butyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, fluorine,chlorine, bromine, trifluoromethyl, trifluoromethoxy, hydroxy,hydroxymethyl, cyano, amino, aminomethyl, methylamino, anddimethylamino; and more preferably selected from the group consisting offluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, and amino.Useful compounds include those where R¹⁴ is unsubstituted phenyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein R¹¹ and R¹² are bothhydrogen and R¹³ and R¹⁴ together with the nitrogen atom to which theyare attached form a 4- to 7-membered heterocyclic ring. Useful compoundsof the present invention include those where R¹³ and R¹⁴ together withthe nitrogen atom form pyrrolidinyl, piperidinyl, or hexahydroazepinyl,and preferably piperidinyl or hexahydroazepinyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z is Z⁵. In one embodiment,compounds useful in the present invention are compounds of any ofFormulae I-III, wherein Z⁵ is aryl substituted with at least one ofalkoxycarbonyl, haloalkyl, carboxy, aminocarbonyl, alkylaminocarbonyl,or dialkylaminocarbonyl, wherein said aryl can be further optionallysubstituted. Useful compounds of the present invention include thosewhere Z⁵ is C₆₋₁₀ aryl substituted with at last one of alkoxycarbonyl orhaloalkyl, wherein said C₆₋₁₀ aryl can be further optionallysubstituted. Preferably, Z⁵ is phenyl substituted with at least one ofC₁₋₄ alkoxycarbonyl or trifluoromethyl, preferably one or two C₁₋₄alkoxycarbonyl, especially methoxycarbonyl or ethoxycarbonyl, ortrifluoromethyl, and wherein said phenyl can be further optionallysubstituted with one or more, preferably one or two, substituents.Useful optional substituents are selected from the group consisting ofhalogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, dialkylamino, carboxy,aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl; preferablyselected from the group consisting of halogen, C₁₋₄ alkyl,halo(C₁₋₄)alkyl, C₁₋₄ alkoxy, halo(C₁₋₄)alkoxy, hydroxy,hydroxy(C₁₋₄)alkyl, cyano, amino, amino(C₁₋₄)alkyl, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, aminocarbonyl, C₁₋₄ alkylaminocarbonyl, anddi(C₁₋₄)alkylaminocarbonyl; more preferably selected from the groupconsisting of fluoro, bromo, chloro, methyl, ethyl, propyl, isopropyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, hydroxy,hydroxymethyl, cyano, amino, aminomethyl, methylamino, dimethylamino,carboxy, aminocarbonyl, methylaminocarbonyl, and dimethylaminocarbonyl.

In one embodiment, compounds useful in the present invention arecompounds of any of Formulae I-III, wherein Z⁵ is heteroaryl substitutedwith at least one of alkoxycarbonyl, haloalkyl, carboxy, aminocarbonyl,alkylaminocarbonyl, or dialkylaminocarbonyl, wherein said heteroaryl canbe further optionally substituted. Useful compounds of the presentinvention include those where Z⁵ is heteroaryl having 5-10 ring atomssubstituted with at last one of alkoxycarbonyl or haloalkyl, whereinsaid heteroaryl can be further optionally substituted. Preferably, Z⁵ ispyridyl (pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), especiallypyridin-2-yl, substituted with at least one of C₁₋₄ alkoxycarbonyl ortrifluoromethyl, preferably one or two C₁₋₄ alkoxycarbonyl, especiallymethoxycarbonyl or ethoxycarbonyl, or trifluoromethyl, and wherein saidpyridyl can be further optionally substituted with one or more,preferably one or two, substituents. Useful optional substituents areselected from the group consisting of halogen, alkyl, haloalkyl, alkoxy,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,dialkylamino, carboxy, aminocarbonyl, alkylaminocarbonyl, anddialkylaminocarbonyl; preferably selected from the group consisting ofhalogen, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, C₁₋₄ alkoxy, halo(C₁₋₄)alkoxy,hydroxy, hydroxy(C₁₋₄)alkyl, cyano, amino, amino(C₁₋₄)alkyl, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, carboxy, aminocarbonyl, C₁₋₄alkylaminocarbonyl, and di(C₁₋₄)alkylaminocarbonyl; more preferablyselected from the group consisting of fluoro, bromo, chloro, methyl,ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, hydroxy, hydroxymethyl, cyano, amino, aminomethyl,methylamino, dimethylamino, carboxy, aminocarbonyl, methylaminocarbonyl,and dimethylaminocarbonyl.

Preferably, q is 2 and p is 1 or q is 1 and p is 2; and more preferably,q is 1 and p is 2.

The invention also relates to compounds represented by Formula IV:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein R¹-R⁴, m, p, and q are as defined above. Preferred values forR¹-R⁴, m, p, and q are those described above as preferred for Formula I.

The invention also relates to compounds represented by Formula V:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein R¹-R³, R⁵-R⁷, n, p, and q are as defined above. Preferred valuesfor R¹-R³, R⁵-R⁷, n, p, and q are those described above as preferred forFormula I.

The invention also relates to compounds represented by Formula VI:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein R¹-R³, R⁸-R¹⁰, p, q, and r are as defined above. Preferredvalues for R¹-R³, R⁸-R¹⁰, p, q, and r are those described above aspreferred for Formula I.

The invention also relates to compounds of Formula VII:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein R¹-R³, R¹¹-R¹⁴, p, q, and s are as defined above. Preferredvalues for R¹-R³, R¹¹-R¹⁴, p, q, and s are those described above aspreferred for Formula I.

The invention also relates to compounds of Formula VIII:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein R¹-R³, Z⁵, p, and q are as defined above. Preferred values forR¹-R³, Z⁵, p, and q are those described above as preferred for FormulaI.

Exemplary preferred compounds useful in the present invention include:

-   2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}propionic    acid ethyl ester;-   2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}-2-methylpropionic    acid ethyl ester;-   {4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}acetic    acid 4-chlorophenyl ester;-   2-{-4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}benzoic    acid methyl ester;-   4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-3′-carboxylic    acid ethyl ester;-   3-{-4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}-5-fluorobenzoic    acid ethyl ester;-   4-{-4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}benzoic    acid ethyl ester;-   N-[1-(3,5-bis-(trifluoromethyl)phenyl)piperidin-1-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;-   N-[1-(2-amino-ethyl)-piperidin-4-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;-   N-(2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]piperidin-1-yl}ethyl)-4-fluorobenzamide;-   N-(2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]piperidin-1-yl}ethyl)-3,5-bis(trifluoromethyl)phenylbenzamide;-   N-Isopropyl-N-[1-(3-oxo-3-piperidin-1-yl-propyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide;-   N-(2-Chloro-4-fluorophenyl)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-isobutyramide;-   2-{4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-N-(4-fluoro-phenyl)-isobutyramide;-   3-{4-[Isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}-N-tert-butyl-butyramide;-   N-Isopropyl-N-[1-(2-oxo-1-phenyl-pyrrolidin-3-yl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide;-   2-{-4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]piperidin-1-yl}-N-phenyl-propionamide;-   N-[1-(2-Azepan-1-yl-2-oxo-ethyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide;-   N-Isopropyl-N-[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide;-   N-Cycloheptyl-2-{-4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide;-   N-Bicyclo[2.2.1]hept-2-yl-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide;-   2-{4-[Isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-N-(tetrahydrofuran-3-yl)-acetamide;-   N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-2-{-4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide;

and the pharmaceutically acceptable salts, prodrugs and solvatesthereof.

Useful cycloalkyl or monocycloalkyl groups are selected from C₃₋₁₂cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

As used herein, the term “bicycloalkyl” refers to saturated alicyclichydrocarbon systems consisting of two rings and having two or more atomsin common. Useful bicycloalkyl groups are selected from C₄₋₁₂bicycloalkyl. Typical bicycloalkyl groups include bicyclobutyl,bicyclopentyl, bicyclohexyl, bicycloheptyl, and bicyclooctyl, especiallybicyclo[3.1.0]hept-3-yl and bicyclo[2.2.1]hept-2-yl.

As used herein, the term “tricycloalkyl” refers to saturated alicyclichydrocarbon systems consisting of three rings and having two or moreatoms in common. Useful tricycloalkyl groups are selected from C₆₋₁₄tricycloalkyl. Typical tricycloalkyl groups include tricyclohexyl,tricycloheptyl, tricyclooctyl, tricyclononyl, and tricyclodecyl,especially tricyclo[2.2.1.0]heptyl.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups are selected from straight-chained and branchedC₁₋₁₀ alkyl groups, more preferably straight chain C₁₋₆ alkyl groups andbranched chain C₁₋₆ alkyl groups, and more preferably straight chainC₁₋₄ alkyl groups and branched chain C₁₋₄ alkyl groups. Typical C₁₋₁₀alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl,among others.

Useful alkenyl groups are selected from C₂₋₆ alkenyl groups, preferablyC₂₋₄ alkenyl. Typical C₂₋₆ alkenyl groups include ethenyl, propenyl,isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl. Typical C₂₋₄alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, andsec-butenyl.

Useful alkynyl groups are selected from C₂₋₆ alkynyl groups, preferablyC₂₋₄ alkynyl. Typical C₂₋₆ alkynyl groups include ethynyl, propynyl,butynyl, 2-butynyl, pentynyl, and hexynyl groups. Typical C₂₋₄ groupsinclude ethynyl, propynyl, butynyl, and 2-butynyl groups.

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by any of the C₆₋₁₄ aryl groups mentioned below.Typical arylalkyl groups include benzyl, phenethyl, and naphthylmethyl.

Useful arylalkenyl groups include any of the above-mentioned C₂₋₆alkenyl groups substituted by any of the C₆₋₁₄ aryl groups mentionedbelow.

Useful arylalkynyl groups include any of the above-mentioned C₂₋₆alkynyl groups substituted by any of the C₆₋₁₄ aryl groups mentionedbelow.

Useful cycloalkylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned cycloalkylgroups.

Useful haloalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by one or more fluorine, chlorine, bromine or iodineatoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups).

Useful hydroxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by hydroxy (e.g., hydroxymethyl, hydroxyethyl,hydroxypropyl and hydroxybutyl groups, and especially hydroxymethyl,1-hydroxyethyl, 2-hydroxypropyl, 3-hydroxybutyl, and2-hydroxy-1-methylpropyl).

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy,iso-propoxy, butoxy, tert-butoxy, iso-butoxy, sec-butoxy, andpentyloxy).

Useful alkoxyalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted with any of the above-mentioned alkoxy groups (e.g.,methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl,ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl,iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl).

Useful haloalkoxy groups include oxygen substituted by one of the C₁₋₁₀haloalkyl groups mentioned above (e.g., fluoromethoxy, difluoromethoxy,and trifluoromethoxy).

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,isoindenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups, morepreferably phenyl, naphthyl, and biphenyl groups.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms, with 6, 10 or 14 it electrons shared in a cyclic array, andcontaining carbon atoms and 1, 2, or 3 heteroatoms independently chosenfrom oxygen, nitrogen and sulfur. Examples of heteroaryl groups includethienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl,benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl,xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl,indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl,furazanyl, and phenoxazinyl. Preferred heteroaryl groups include thienyl(e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl),pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g.,2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-6-yl),thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl),isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, andisothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl,oxazol-5-yl), and isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, and5-isoxazolyl).

Useful heteroarylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the heteroaryl groups mentionedbelow. Useful values include, for example, pyridin-2-ylmethyl,pyridin-3-ylmethyl, pyridin-4-ylmethyl.

The terms “heterocyclic” and “heterocyclo” are used herein to meansaturated or partially unsaturated 3-7 membered monocyclic, or 7-10membered bicyclic ring system, which consist of carbon atoms and fromone to four heteroatoms independently selected from the group consistingof O, N, and S, wherein the nitrogen and sulfur heteroatoms can beoptionally oxidized, the nitrogen can be optionally quaternized, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring, and wherein theheterocyclic ring can be substituted on a carbon atom or on a nitrogenatom if the resulting compound is stable. A 3-membered heterocyclic ringcan contain one heteroatom, a 4-membered ring can contain one or twoheteroatoms, a 5-membered ring can contain up to 4 heteroatoms, a6-membered ring can contain up to 5 heteroatoms, and a 7-membered ringcan contain up to 5 heteroatoms. Examples include, but are not limitedto, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolinyl,pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, tetrahydrothienyl,imidazolidinyl, hexahydropyrimidinyl, benzo[1,3]-dioxole,benzodiazepines, and the like.

As used herein, the term “amino” or “amino group” refers to —NH₂.

Useful aminoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted with an amino group.

Useful alkylamino and dialkylamino groups are —NHR¹⁵ and —NR¹⁵R¹⁶,respectively, wherein R¹⁵ and R¹⁶ are each independently selected from aC₁₋₁₀ alkyl group.

Useful hydroxyalkylamino groups are —NHR¹⁵, wherein R¹⁵ is any of theabove-mentioned hydroxyalkyl groups.

Useful alkylaminoalkyl and dialkylaminoalkyl groups are any of theabove-mentioned C₁₋₁₀ alkyl groups substituted by any of theabove-mentioned alkylamino and dialkylamino groups, respectively.

Useful aminocarbonylalkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups substituted with an aminocarbonyl group, i.e.,—C(O)NH₂.

Useful alkylcarbonyl groups include a carbonyl group, i.e., —C(O)—,substituted by any of the above-mentioned C₁₋₁₀ alkyl groups.

Useful alkylcarbonylamino groups include any of the above-mentionedalkylcarbonyl groups attached to an amino nitrogen, such asmethylcarbonylamino.

Useful alkoxycarbonyl groups include a carbonyl group, i.e., —C(O)—,substituted by any of the above-mentioned C₁₋₁₀ alkoxy groups.

Useful alkoxycarbonylalkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups substituted by an alkoxycarbonyl group defined above.

Useful alkylaminocarbonyl groups include a carbonyl group, i.e., —C(O)—,substituted by any of the above-mentioned alkylamino groups.

Useful dialkylaminocarbonyl groups include a carbonyl group, i.e.,—C(O)—, substituted by any of the above-mentioned dialkylamino groups.

Useful alkylsulfonylaminoalkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups substituted by an alkyl-SO₂—NH— group.

Useful mercaptoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by a —SH group.

As used herein, the term “carboxy” refers to —COOH.

Useful carboxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by —COOH.

Useful cyanoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by —CN.

As used herein, the term “ureido” refers to —NH—C(O)—NH₂.

As used herein, the term “azido” refers to —N₃.

As used herein, the term “optionally substituted” refers to a group thatmay be unsubstituted or substituted.

Optional substituents on optionally substituted groups, when nototherwise indicated, include one or more groups, preferably 1, 2, or 3groups, independently selected from the group consisting of halo,halo(C₁₋₆)alkyl, aryl, heterocycle, cycloalkyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl, cycloalkyl(C₁₋₆)alkyl, heterocyclo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl,alkoxy(C₁₋₆)alkyl, nitro, amino, ureido, cyano, alkylcarbonylamino,hydroxy, thiol, alkylcarbonyloxy, azido, alkoxy, carboxy, aminocarbonyl,and C₁₋₆ alkylthiol groups mentioned above. Preferred optionalsubstituents include halo, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, alkoxy, and amino.

The invention disclosed herein is also meant to encompass prodrugs ofany of the disclosed compounds. As used herein, prodrugs are consideredto be any covalently bonded carriers that release the active parent drugin vivo. In general, such prodrugs will be a functional derivative of acompound of Formula I-VIII which is readily convertible in vivo, e.g.,by being metabolized, into the required compound of Formula I-VIII.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described in, for example, Design of Prodrugs,H. Bundgaard ed., Elsevier (1985); “Drug and Enzyme Targeting, Part A,”K. Widder et al. eds., Vol. 112 in Methods in Enzymology, Academic Press(1985); Bundgaard, “Design and Application of Prodrugs,” Chapter 5 (pp.113-191) in A Textbook of Drug Design and Development, P.Krogsgaard-Larsen and H. Bundgaard eds., Harwood Academic Publishers(1991); Bundgaard et al., Adv. Drug Delivery Revs. 8:1-38 (1992);Bundgaard et al., J. Pharmaceut. Sci. 77:285 (1988); and Kakeya et al.,Chem. Pharm. Bull. 32:692 (1984). Non-limiting examples of prodrugsinclude esters or amides of compounds of any of Formulae I-VIII havinghydroxyalkyl or aminoalkyl as a substituent, and these may be preparedby reacting such parent compounds with anhydrides such as succinicanhydride.

The invention disclosed herein is also intended to encompass any of thedisclosed compounds being isotopically-labelled (i.e., radiolabeled) byhaving one or more atoms replaced by an atom having a different atomicmass or mass number. Examples of isotopes that can be incorporated intothe disclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, andpreferably ³H, ¹¹C, and ¹⁴C. Isotopically-labeled compounds of thepresent invention can be prepared by methods known in the art.

The present invention is also directed specifically to ³H, ¹¹C, or ¹⁴Cradiolabeled compounds of any of Formulae I-VIII, as well as theirpharmaceutically acceptable salts, prodrugs and solvates, and the use ofany such compounds as radioligands for their binding site on the calciumchannel. For example, one use of the labeled compounds of the presentinvention is the characterization of specific receptor binding. Anotheruse of a labeled compound of the present invention is an alternative toanimal testing for the evaluation of structure-activity relationships.For example, the receptor assay may be performed at a fixedconcentration of a labeled compound of the invention and at increasingconcentrations of a test compound in a competition assay. For example, atritiated compound of any of Formulae I-VIII can be prepared byintroducing tritium into the particular compound, for example, bycatalytic dehalogenation with tritium. This method may include reactinga suitably halogen-substituted precursor of the compound with tritiumgas in the presence of a suitable catalyst, for example, Pd/C, in thepresence or absence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6(1987). ¹⁴C-labeled compounds can be prepared by employing startingmaterials having a ¹⁴C carbon.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present invention is meant toencompass the uses of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers maybe separated according to methods known to those of ordinary skill inthe art in view of the present disclosure. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that theyinclude both E and Z geometric isomers. All tautomers are intended to beencompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treating” or “treatment” is meant to encompass administeringto a subject a compound of the present invention for the purposes ofamelioration or cure, including preemptive and palliative treatment.

The invention disclosed herein also encompasses the use of salts of thedisclosed compounds, including all non-toxic pharmaceutically acceptablesalts thereof of the disclosed compounds. Examples of pharmaceuticallyacceptable addition salts include inorganic and organic acid additionsalts and basic salts. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,cesium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide,phosphate, sulphate and the like; organic acid salts such as citrate,lactate, tartrate, maleate, fumarate, mandelate, acetate,dichloroacetate, trifluoroacetate, oxalate, formate and the like;sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparaginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularcompound of the present invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present invention with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

The invention disclosed herein is also meant to encompass solvates ofany of the disclosed compounds. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present invention with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present invention is 2:1, 1:1 or 1:2,respectively. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances, the solvate can be isolated, such as when one or more solventmolecules are incorporated into the crystal lattice of a crystallinesolid. Thus, “solvate” encompasses both solution-phase and isolatablesolvates. Compounds of any of Formulae I-VIII may be present as solvatedforms with a pharmaceutically acceptable solvent, such as water,methanol, ethanol, and the like, and it is intended that the inventionincludes both solvated and unsolvated forms of compounds of any ofFormulae I-VIII. One type of solvate is a hydrate. A “hydrate” relatesto a particular subgroup of solvates where the solvent molecule iswater. Solvates typically can function as pharmacological equivalents.Preparation of solvates is known in the art. See, for example, M. Cairaet al., J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparation of solvates, hemisolvates, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun.: 603-604(2001). A typical, non-limiting, process of preparing a solvate wouldinvolve dissolving a compound of any of Formulae I-VIII in a desiredsolvent (organic, water, or a mixture thereof) at temperatures aboveabout 20° C. to about 25° C., then cooling the solution at a ratesufficient to form crystals, and isolating the crystals by knownmethods, e.g., filtration. Analytical techniques such as infraredspectroscopy can be used to confirm the presence of the solvent in acrystal of the solvate.

Since compounds of Formulae I-VIII are blockers of calcium (Ca²⁺)channels, a number of diseases and conditions mediated by calcium ioninflux can be treated by employing these compounds (See, e.g., Gould etal., Proc. Natl. Acad. Sci. USA 80:5122-5125 (1983); Schwartz et al.,Am. J. Cardiol. 62:3 G-6G (1988); Ito, M., Ann. Rev. Neurosci. 12:85-102(1989); Nuglisch et al., J. Cereb. Blood Flow Metab. 10:654-659 (1990);Janis, R. J. & Triggle, D. J., Drugs Acting on Calcium Channels, inCalcium Channels: Their Properties, Functions, Regulation and ClinicalRelevance, p. 195-249, Hurwitz et al. eds., CRC Press, London (1991); Huet al., Bioorg. Med. Chem. Lett. 9:2151-2156 (1999); Hu et al., J. Med.Chem. 42:4239-4249 (1999); Hu et al., Bioorg. Med. Chem. 8:1203-1212(2000); Song et al., J. Med. Chem. 43:3474-3477 (2000); Vanegas et al.,Pain 85:9-18 (2000); Wallace, M. S., The Clinical Journal of Pain16:S80-S85 (2000); and Lukyanetz et al., Epilepsia 43:9-18 (2002)). Thepresent invention is thus directed generally to a method for treating adisorder responsive to the blockade of calcium channels, andparticularly the selective blockade of N-type calcium channels, in ananimal suffering from, or at risk of suffering from, said disorder, saidmethod comprising administering to the animal an effective amount of acompound represented by any of defined Formulae I-VIII, or apharmaceutically acceptable salt, prodrug or solvate thereof.

The present invention is further directed to a method of modulatingcalcium channels, especially N-type calcium channels, in an animal inneed thereof, said method comprising administering to the animal atleast one compound represented by any of defined Formulae I-VIII, or apharmaceutically acceptable salt, prodrug or solvate thereof.

More specifically, the present invention provides a method of treatingstroke, the neuronal damage resulting from head trauma, epilepsy, pain(e.g., acute pain, chronic pain, which includes but is not limited toneuropathic pain and inflammatory pain, or surgical pain), migraine, amood disorder, schizophrenia, a neurodegenerative disorder (e.g.,Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson'sdisease), depression, anxiety, a psychosis, hypertension, or cardiacarrhythmia. In one embodiment, the invention provides a method oftreating pain. In another embodiment, the type of pain treated ischronic pain. In another embodiment, the type of pain treated isneuropathic pain. In another embodiment, the type of pain treated isinflammatory pain. In another embodiment, the type of pain treated issurgical pain. In another embodiment, the type of pain treated is acutepain. In another embodiment, the treatment of pain (e.g., chronic pain,such as neuropathic pain or inflammatory pain, acute pain or surgicalpain) is preemptive or palliative treatment of pain. In each instance,such method of treatment requires administering to an animal in need ofsuch treatment an amount of a compound of the present invention that istherapeutically effective in achieving said treatment. In oneembodiment, the amount of such compound is the amount that is effectiveas to block calcium channels in vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 2000; 18: 387-391).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogenous disease state with an unclearetiology. In chronic neuropathic pain, the pain can be mediated bymultiple mechanisms. This type of pain generally arises from injury tothe peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-VIII, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament for treating a disorder responsive to the blockade of calciumchannels (e.g., any of the disorders listed above) in an animalsuffering from said disorder. In one embodiment, the disorder isresponsive to the selective blockade of N-type calcium channels.

Furthermore, the present invention is directed to a method of modulatingcalcium channels, especially N-type calcium channels, in an animal inneed thereof, said method comprising administering to the animal atleast one compound represented by any defined Formulae I-VIII, or apharmaceutically acceptable salt, prodrug or solvate thereof.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-VIII, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament, in particular a medicament for modulating calcium channels,especially N-type calcium channels, in an animal in need thereof.

Synthesis of Compounds

The compounds of the present invention may be prepared using methodsknown to those skilled in the art in view of this disclosure. Forexample, compounds of Formula I where Z is Z¹ can be prepared as shownin Scheme 1.

where R¹, R², and R³ are as defined for Formula I and R′ is alkyl.

Compounds of Formula I where Z is Z² can be prepared as shown in Scheme2:

where R¹, R², R³, R⁵, R⁶, R⁷ and n are as defined above.

Compounds of Formula I where Z is Z³ and R⁸ and R⁹ together form ═O canbe prepared as shown in Scheme 3:

where R¹, R², R³, R¹⁰ and r are as defined above.

Compounds of Formula I where Z is Z³ and R⁸ and R⁹ are both hydrogen canbe prepared as shown in Scheme 4:

where R¹, R², R³, R¹⁰ and r are as defined above.

Compounds of Formula I where Z is Z⁴ can be prepared as follows:

where R¹-R³, and R¹¹-R¹⁴ are as defined for Formula I and X is halogen.

Compounds of Formula I where Z is Z² or Z⁴ can be prepared as shown inScheme 6:

where R¹-R³ and R¹¹-R¹⁴ are as defined for Formula I and X is halogen.

A method for preparing compounds of Formula I where Z is Z⁵ can befollows:

where R¹, R², and R³ are as defined for Formula I, Y is N or CH, X ishalogen, W is, for example, H, F, Cl, or CF₃, and R″ is C₁₋₄ alkyl.

Compounds of Formulae I-VIII where q is 0 and p is 1, q is 1 and p is 1,q is 2 and p is 1, q is 3 and p is 1, or q is 2 and p is 2 can beprepared using methods analogous to those described above forcorresponding compounds where q is 1 and p is 2.

Testing of Compounds

Compounds of the present invention were assessed by calcium mobilizationand/or electrophysiological assays for calcium channel blocker activity.One aspect of the present invention is based on the use of the compoundsherein described as N-type calcium channel blockers. In one aspect ofthe present invention, it has been found that certain compounds hereindescribed show selectivity as N-type calcium channel blockers. Basedupon this property, these compounds are considered useful in treatingstroke, neuronal damage resulting from head trauma, migraine, epilepsy,a mood disorder, schizophrenia, a neurodegenerative disorder (such as,e.g., Alzheimer's disease, ALS, or Parkinson's disease), a psychosis,depression, anxiety, hypertension, or cardiac arrhythmia. The compoundsof the present invention are also expected to be effective in treatingpain, such as acute pain, chronic pain, which includes but is notlimited to neuropathic pain and inflammatory pain, or surgical pain.

More specifically, the present invention is directed to compounds ofFormulae I-VIII that are blockers of calcium channels. According to thepresent invention, those compounds having preferred N-type calciumchannel blocking properties exhibit an IC₅₀ of about 100 μM or less inthe calcium mobilization and/or electrophysiological assays describedherein. Preferably, the compounds of the present invention exhibit anIC₅₀ of 10 μM or less. More preferably, the compounds of the presentinvention exhibit an IC₅₀ of about 6 μM or less. Most preferably, thecompounds of the present invention exhibit an IC₅₀ of about 1.0 μM orless. Compounds of the present invention can be tested for their N-typeand L-type Ca²⁺ channel blocking activity by the following calciummobilization and/or electrophysiological assays.

In one embodiment, compounds useful in the present invention are thoserepresented by any one of Formulae I-VIII that exhibit selectivity forN-type calcium channels over L-type calcium channels in the calciummobilization and/or electrophysiological assays described herein. Thephrase “selectivity for N-type calcium channels over L-type calciumchannels” is used herein to mean that the ratio of an IC₅₀ for L-typechannel blocking activity for a compound of the present invention overan IC₅₀ for N-type channel blocking activity for the same compound ismore than 1, i.e., LTCC IC₅₀/NTCC IC₅₀>1. Preferably, compounds of thepresent invention exhibit an LTCC IC₅₀/NTCC IC₅₀ ratio of about 2 ormore, about 10 or more, about 20 or more, about 30 or more, about 50 ormore, or about 100 or more.

Calcium Mobilization and Electrophysiological Assay Protocols:

Cell maintenance and differentiation. Unless noted otherwise, cellculture reagents were purchased from Mediatech of Herndon, Md. IMR32cells (American Type Culture Collection, ATCC, Manassas, Va.) wereroutinely cultured in growth medium consisting of minimum essentialmedium containing 10% fetal bovine serum (FBS, Hyclone, Logan, Utah),100 U/mL penicillin, 100 μg/mL streptomycin, 2 mM L-glutamine, 1 mMsodium pyruvate, and 1×MEM non-essential amino acids. 80-90% confluentflasks of cells were differentiated using the following differentiationmedium: Growth medium plus 1 mM dibutyryl cyclic AMP (Sigma, St. Louis,Mo.), and 2.5 μM bromodeoxyuridine (Sigma). Cells were differentiatedfor 8 days by replacing differentiation medium every 2-3 days.

A7r5 (ATCC) cells were maintained and routinely cultured in A7r5 growthmedium consisting of Dulbecco's Modified Eagles Medium containing 10%FBS, 100 U/mL penicillin, 100 μg/mL streptomycin, 4 mM L-glutamine, and0.15% sodium bicarbonate. 80-90% confluent flasks of cells weredifferentiated using the following differentiation medium: A7r5 GrowthMedium plus 1 mM dibutyryl cyclic AMP (Sigma). Cells were differentiatedfor 8 days by replacing differentiation medium every 2-3 days.

Recombinant human embryonal kidney cells (HEK293, ATCC) stablytransfected with either N-type calcium channel (NTCC) subunits (α1b (SEQID NOs: 13 to 15), α2δ (SEQ ID Nos: 16, 17), and β3 (SEQ ID NOs:18 to20)) or L-type calcium channel (LTCC) subunits (α1c (SEQ ID NOs:21, 22),α2δ, and β1 (SEQ ID NOs:23 to 25)) were routinely cultured in growthmedium consisting of Dulbecco's Modified Eagles Medium containing 10%FBS, 100 U/mL penicillin, 100 μg/mL streptomycin, 4 mM L-glutamine, 500μg/mL geneticin (G418), 20 μg/mL Blasticidin S (InVivogen, San Diego,Calif.) and 500 μg/mL zeocin (InVivogen).

FLIPR Calcium Mobilization Assay for N-type Calcium Channel. One dayprior to performing this assay, differentiated IMR32 cells were treatedwith 1× CellStripper, and seeded on poly-D-lysine-coated 96-wellclear-bottom black plates (Becton Dickinson, Franklin Lakes, N.J.) at200,000 cells/well. On the day of the assay, the cell plates were washedwith IMR32 buffer (127 mM NaCl, 1 mM KCl, 2 mM MgCl₂, 700 μM NaH₂PO₄, 5mM CaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM glucose, pH 7.4), thenpre-stimulated with KCl and loaded as follows: 0.05 mL of IMR32 buffer,0.05 mL of each compound tested diluted in IMR32 buffer containing 20 μMnitrendipine (Sigma), and 0.1 mL KCl dissolved in IMR32 buffer, plusFluo-4 were added (3 μM final concentration, Molecular Probes, Eugene,Oreg.). Final test compound concentrations ranged from about 846 pM toabout 17 μM, final nitrendipine concentration was 5 μM, and final KClconcentration was 90 mM. After 1 hour, the cells were washed twice with0.05 mL of each compound tested in nitrendipine-containing IMR32 buffer(no KCl or Fluo-4), and then replaced with 0.1 mL of each compoundtested in nitrendipine-containing IMR32 buffer. Plates were thentransferred to a Fluorimetric Imaging Plate Reader (FLIPR⁹⁶, MolecularDevices, Inc., Sunnyvale, Calif.) for assay. The FLIPR measured basalFluo-4 fluorescence for 315 seconds (i.e., 5 minutes and 15 seconds),then added 0.1 mL KCl agonist dissolved in IMR32 buffer and measuredfluorescence for another 45 seconds. Final test compound concentrationson the cells after FLIPR read ranged from about 846 pM to about 17 μM,final nitrendipine concentration was 5 μM, and final KCl concentrationwas 90 mM. Data were collected over the entire time course and analyzedusing Excel, Graph Pad Prism (version 3.02, Graph Pad, San Diego,Calif.), or an in-house non-linear regression analysis software.

FLIPR Calcium Mobilization Assay for L-type Calcium Channel. One dayprior to performing this assay, HEK293 cells stably expressingrecombinant rat L-type calcium channel (LTCC) subunits (α1c, α2δ, andβ1) were trypsinized, then seeded on poly-D-lysine-coated 96-wellclear-bottom black plates (Becton Dickinson, Franklin Lakes, N.J.) at75,000 cells/well. On the day of the assay, the plates were washed withLTCC wash buffer (127 mM NaCl, 2 mM MgCl₂, 700 μM NaH₂PO₄, 5 mM CaCl₂, 5mM NaHCO₃, 8 mM HEPES, 10 mM glucose, pH 7.4), then loaded with 0.1 mLof LTCC wash buffer containing Fluo-4 (3 μM final concentration,Molecular Probes, Eugene, Oreg.). After 1 hour, the cells were washedwith 0.1 mL LTCC wash buffer and resuspended in 0.05 mL LTCC assaybuffer (same composition as LTCC wash buffer). Plates were thentransferred to a FLIPR⁹⁶ for assay. The FLIPR measured basal Fluo-4fluorescence for 15 seconds, then added 0.05 mL of each compound testeddiluted in LTCC assay buffer at final concentrations ranging from about846 pM to about 17 M. Fluo-4 fluorescence was then measured for 5minutes. 0.1 mL KCl agonist dissolved in LTCC assay buffer was thenadded to the cells to produce a final concentration of 90 mM KCl, andfluorescence was measured for another 45 seconds. Data were collectedover the entire time course and analyzed using Excel, Graph Pad Prism,or an in-house regression analysis software.

Alternative FLIPR Calcium Mobilization Assay for L-type Calcium Channel.Alternatively, the following cell line and procedure may be used for theFLIPR calcium mobilization assay for L-type calcium channel. One dayprior to performing this assay, differentiated A7r5 cells aretrypsinized, then seeded on tissue culture treated 96-well clear-bottomblack plates (Becton Dickinson, Franklin Lakes, N.J.) at a dilution of1:1 from a confluent T150 cm² flask. On the day of the assay, the platesare washed with A7r5 wash buffer (127 mM NaCl, 2 mM MgCl₂, 700 μMNaH₂PO₄, 5 mM CaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM glucose, pH 7.4),then loaded with 0.1 mL of A7r5 wash buffer containing Fluo-4 (3 μMfinal concentration, Molecular Probes, Eugene, Oreg.). After 1 hour, thecells are washed with 0.1 mL A7r5 wash buffer and resuspended in 0.05 mLA7r5 assay buffer that is composed of A7r5 wash buffer plus 50 μMvalinomycin (Sigma). Plates are then transferred to a FLIPR⁹⁶ for assay.The FLIPR measures basal Fluo-4 fluorescence for 15 seconds, then adds0.05 mL of each compound tested diluted in A7r5 assay buffer at finalconcentrations ranging from about 846 pM to about 17 μM. Fluo-4fluorescence is then measured for 5 minutes. 0.1 mL KCl agonistdissolved in A7r5 assay buffer is then added to the cells to produce afinal concentration of 90 mM KCl, and fluorescence was measured foranother 45 seconds. Data were collected over the entire time course andanalyzed using Excel, Graph Pad Prism, or an in-house regressionanalysis software.

Cloning of N- and L-type calcium channel subunit open reading framecDNAs. Five cDNAs encoding subunits of the rat N- or L-type calciumchannels were cloned by PCR amplification in order to reconstitutefunctional channels in a heterologous system. These were the alpha1b(α1b; SEQ ID NO: 14), beta1 (β1; SEQ ID NO:24), beta3 (β3; SEQ IDNO:19), alpha2delta (α2δ; SEQ ID NO:16), and alpha1c (α1c; SEQ ID NO:21)subunit cDNAs. The alpha1b subunit cDNA has been described by Dubel etal. in Proc. Natl. Acad. Sci. U.S.A 89: 5058-5062 (1992). The beta1subunit cDNA has been described by Pragnell et al. in FEBS Lett. 291:253-258 (1991). The beta3 subunit cDNA has been described by Castellanoet al. in J. Biol. Chem. 268: 12359-12366 (1993). The alpha2deltasubunit cDNA has been described by Kim et al. in Proc. Natl. Acad. Sci.U.S.A. 89: 3251-3255 (1992). The alpha1c subunit cDNA has been describedby Koch et al. in J. Biol. Chem. 265: 17786-17791 (1990).

The 7.0 kb cDNA containing the entire alb open reading frame (ORF) wasPCR amplified as two overlapping cDNA fragments, i.e., a 2.7 kb 5′fragment and a 4.4 kb 3′ fragment. The 5′ fragment was amplified fromrat brain cDNA using primers 1 (SEQ ID NO:1, TABLE 1) and 2 (SEQ IDNO:2, TABLE 1), and the 3′ fragment was amplified from rat spinal cordcDNA using primers 3 (SEQ ID NO:3, TABLE 1) and 4 (SEQ ID NO:4, TABLE1). The two fragments were joined by ligation at a common restrictionsite to create the entire 7.0 kb cDNA. This ORF encodes the proteinisoform generated by alternative splicing termed “+A ΔSFMG ΔET”according to the nomenclature of Lin et al. (Neuron 18: 153-166 (1997)).The entire cDNA was sequenced with redundant coverage on both strands.The cDNA was then inserted into the mammalian expression vectorpcDNA6.2DEST (Invitrogen, Carlsbad Calif.) by homologous recombinationusing the Gateway system (Invitrogen) resulting in SEQ ID NO:13.

The 1.8 kb cDNA encoding the β1 subunit, the 1.45 cDNA encoding thebeta3 subunit, and the 3.3 kb cDNA encoding the alpha2delta subunit werecloned by PCR amplification from rat spinal cord cDNA (β1) or brain cDNA(β3, α2δ). Primers 5 (SEQ ID NO:5, TABLE 1) and 6 (SEQ ID NO:6, TABLE 1)were used for the β1 cDNA amplification; primers 7 (SEQ ID NO:7,TABLE 1) and 8 (SEQ ID NO:8, TABLE 1) were used for the β3 cDNAamplification; and primers 9 (SEQ ID NO:9, TABLE 1) and 10 (SEQ IDNO:10, TABLE 1) were used for the α2δ cDNA amplification. PCR productswere subcloned and fully sequenced on both strands. Clones matching thereference sequence (β1: NM_(—)017346; β3: NM_(—)012828; α2δ: M86621) andthe gene's GenBank rat genomic DNA sequences were recombined into themammalian expression vector pcDNA3.2DEST (β1, β3) or pcDNA3.1-Zeo (α2δ),which had been modified to a vector compatible with the Gatewayrecombination system using the Gateway vector adaptor kit (Invitrogen)resulting in SEQ ID NOs:23, 18 and 16, respectively. Properrecombination was confirmed by sequencing of recombinogenic regions. Forβ3 expression vector, proper protein expression was confirmed by Westernblot analysis of lysates of transfected HEK293 cells using a rabbitpolyclonal antiserum directed against the rat β3 subunit (USABiological).

The 6.5 kb cDNA encoding the L-type calcium channel α1c subunit wascloned by PCR amplification from rat heart cDNA using primers 11 (SEQ IDNO:11, TABLE 1) and 12 (SEQ ID NO:12, TABLE 1). The PCR fragment wassubcloned and fully sequenced on both strands to confirm its identity. Aclone matching consensus reference sequence AF394939 and rat genomic DNAsequences was recombined into the mammalian expression vectorpcDNA6.2DEST. Sequences around the recombinogenic region were sequencedto confirm accurate recombination into the expression vector.

TABLE 1 PRIMER SEQUENCE SEQ ID NO. CACC ATG GTC CGC TTC GGG GAC 1CCG TTC AGT GGC CTC CTC C 2 C TAG CAC CAG TGA TCC TGG TCTG 3AGT GCG TTG TGA GCG CAG TA 4 CAC CAT GGT CCA GAA GAG CGG 5TCTCAGCGGATGTAGACGCCT 6 CAC CAT GTA TGA CGA CTC CTA C 7GGT GGT CAG TAG CTG TCC TTA GG 8 CAC CAT GGC TGC TGG CTG CCT 9AGA GGG TCA CCA TAG ATA GTG TCT G 10 CACCATGATTCGGGCCTTCGCT 11AGCCTGCGGACTACAGGTTGCTGAC 12

N-type Recombinant Cell Line Development. N-type calcium channelexpressing HEK-293 cells were created in two stages. Stage 1 was createdas follows. The rat α1b, and β3 cDNA expression constructs (2.5 μg each)were co-transfected into human embryonic kidney (HEK-293) cells byLipofectamine Plus reagent (Invitrogen), as per manufacturer'sinstructions. 24 hours later, cells were split in limiting dilution intomultiple 96-well plates in selection media containing 20 μg/mLblasticidin and 500 μg/mL geneticin, and incubated for 3 weeks at 37°C., 5% CO₂, 95% humidity. Plates containing ≦1 clone per well werecultured until wells positive for single clones were confluent.Individual clones were then arrayed into columns of a destination96-well plate, and partly split into 6-well plates for culturemaintenance. Array plates were washed once with IMR32 buffer and cellsloaded for 1 hour with 0.1 mL of IMR32 buffer containing Fluo-4 (3 μMfinal concentration, Molecular Probes). Then they were washed twice with0.1 mL of IMR32 buffer, and replaced with 0.1 mL IMR32 buffer. Plateswere then transferred to a FLIPR⁹⁶ for assay. The FLIPR measured basalFluo-4 fluorescence for 315 seconds, then added 0.1 mL KCl agonistdissolved in IMR32 buffer and measured fluorescence for another 45seconds. Final KCl concentration was 90 mM. Data were collected over theentire time course and analyzed using Excel, Graph Pad Prism, orActivity Base (version 5.1, IDBS, Parsippany, N.J.) software. The clonewith the greatest signal-to-noise ratio, best stability of response withpassage number, and best adhesion to PDL precoated plates (BectonDickinson) was expanded, characterized and used for stage 2 cell linedevelopment.

Stage 2 of N-type cell line development was carried out as follows. Therat α2δ cDNA expression construct (5 μg each) was transfected into thestage 1 N-type clonal cell line by Lipofectamine Plus reagent(Invitrogen), as per manufacturer's instructions. 24 hours later, cellswere split in limiting dilution into multiple 96-well plates inselection media containing 20 μg/mL blasticidin, 500 μg/mL geneticin,and 250 μg/mL zeocin and incubated for 3 weeks at 37° C., 5% CO₂, 95%humidity. Plates containing ≦1 clone per well were cultured and handledaccording to the same steps and procedures described above for the stage1 cell line. The three clones with the greatest signal-to-noise, beststability of response with passage number, and best adhesion to PDLprecoated plates (Becton Dickinson) were expanded, characterized andtested in electrophysiology for the best current size, N-typepharmacology, N-type characteristic current-voltage relationship andkinetics as described below.

L-type Recombinant Cell Line Development. L-type calcium channelexpressing HEK-293 cells were created in two stages. Stage 1 was createdas follows. The rat α1c, and β1 cDNA expression constructs (2.5 μg each)were co-transfected into human embryonic kidney (HEK-293) cells byLipofectamine Plus reagent (Invitrogen), as per manufacturer'sinstructions. 24 hours later, cells were split in limiting dilution intomultiple 96-well plates in selection media containing 20 μg/mLblasticidin and 500 μg/mL geneticin, and incubated for 3 weeks at 37°C., 5% CO₂, 95% humidity. Plates containing ≦1 clone per well werecultured until wells positive for single clones were confluent.Individual clones were then arrayed into columns of a destination96-well plate, and partly split into 6-well plates for culturemaintenance. Array plates were washed once with LTCC wash (or assay)buffer and cells loaded for 1 hour with 0.1 mL of LTCC buffer containingFluo-4 (3 μM final concentration, Molecular Probes). Then they werewashed twice with 0.1 mL of LTCC buffer, and replaced with 0.1 mL LTCCbuffer. Plates were then transferred to a FLIPR⁹⁶ for assay. The FLIPRmeasured basal Fluo-4 fluorescence for 315 seconds, then added 0.1 mLKCl agonist dissolved in LTCC buffer and measured fluorescence foranother 45 seconds. Final KCl concentration was 90 mM. Data werecollected over the entire time course and analyzed using Excel, GraphPad Prism, or Activity Base software. The clone with the greatestsignal-to-noise ratio, best stability of response with passage number,and best adhesion to PDL precoated plates (Becton Dickinson) wasexpanded, characterized and used for stage 2 cell line development.

Stage 2 of L-type cell line development was carried out as follows. Therat α2δ cDNA expression construct (5 μg each) was transfected into thestage 1 L-type clonal cell line by Lipofectamine Plus reagent(Invitrogen), as per manufacturer's instructions. 24 hours later, cellswere split in limiting dilution into multiple 96-well plates inselection media containing 20 μg/mL blasticidin, 500 μg/mL geneticin,and 250 μg/mL zeocin and incubated for 3 weeks at 37° C., 5% CO₂, 95%humidity. Plates containing ≦1 clone per well were cultured and handledaccording to the same steps and procedures described above for the stage1 cell line. The three clones with the greatest signal-to-noise, beststability of response with passage number, and best adhesion to PDLprecoated plates (Becton Dickinson) were expanded and characterized.

N-type Electrophysiology in Recombinant Cells. For electrophysiologicalrecording, the cells expressing α1b, β3 and α2δ subunits were seeded on35-mm culture Petri dishes at a density of approximately 10⁴ cells/dishand kept in an incubator for up to three days for subsequent recordings.For recordings, the dishes were positioned on the stage of an invertedmicroscope (Nikon, Eclipse E600, Japan) and superfused with a bathsolution comprised of BaCl₂ (11 mM), MgCl₂ (1.5 mM), HEPES (10 mM), TEAchloride (120 mM), glucose (10 mM) adjusted to pH 7.4 with KOH.Whole-cell voltage-clamp recordings were made using conventionalpatch-clamp techniques (Hamill et al., Pfluegers Arch. 391: 85-100(1981)) at room temperature (22-24° C.). The patch-clamp pipettes werepulled from WPI, thick-walled borosilicate glass (WPI, Sarasota, Fla.).Currents were recorded using an Axopatch 200A amplifier (AxonInstruments, Union City, Calif.) and were leak-subtracted (P/4),low-pass filtered (1 kHz, 4-pole Bessel), digitized (20-50-μsintervals), and stored using Digidata 1200 B interface andPclamp8.0/Clampex software (Axon Instruments, Union City, Calif.). Thepipettes were back-filled with internal solution containing CsCl (110mM), MgCl₂ (3 mM), EGTA (3 mM), HEPES (40 mM), Mg-ATP (4 mM), Na₂GTP(0.5 mM), and adjusted to pH 7.2 with CsOH. The pipette resistanceranged from 2 to 3 MOhm and was compensated by 75-80% by the built-inelectronic circuitry.

Currents were elicited by stepping from a holding potential of −90 mV to0 mV for 20 ms every 20 sec. At the −90 mV membrane voltage about 50% ofchannels were in the inactivated state, and thus contact with a blockerwould involve interaction with both resting and inactivated channels.Every drug was applied at 3 to 4 concentrations increasing in acumulative manner. Fractional inhibition levels in steady-state wereused to draw the partial inhibition concentration curves to get the IC₅₀(i.e. concentration causing 50% reduction in the size of the response)values at −90 mV.

Stock solutions of each test compound were prepared using DMSO. Serialdilutions to desired concentrations were done with bath solution;concentration of DMSO in final solutions was 0.1%. Drugs were applied bygravity flow using a plane multi-barrel array shooter positioned 0.5 mmapart from the cell.

All curve fittings were carried out using Origin software (version 5.0,Microcal). A Hill equation was fit to the concentration-inhibitioncurves to determine IC₅₀ values.

N-type Electrophysiology in Neuronal Cells. To determine dissociationconstants in resting versus inactivated state for N-type calciumchannels, neuronal cells that endogenously express N-type calciumchannels can be used. For electrophysiological recording, the neuronalcells expressing N-type calcium channels are seeded on 35-mm culturePetri dishes at a density of approximately 10⁴ cells/dish and kept in anincubator for up to three days for subsequent recordings. Forrecordings, the dishes are positioned on the stage of an invertedmicroscope (Nikon, Eclipse E600, Japan) and superfused with a bathsolution comprised of BaCl₂ (11 mM), MgCl₂ (1.5 mM), HEPES (10 mM), TEAchloride (120 mM), glucose (10 mM) adjusted to pH 7.4 with KOH.Whole-cell voltage-clamp recordings are made using conventionalpatch-clamp techniques (Hamill et al., Pfluegers Arch. 391: 85-100(1981)) at room temperature (22-24° C.). The patch-clamp pipettes arepulled from WPI, thick-walled borosilicate glass (WPI, Sarasota, Fla.).Currents are recorded using an Axopatch 200A amplifier (AxonInstruments, Union City, Calif.) and leak-subtracted (P/4), low-passfiltered (1 kHz, 4-pole Bessel), digitized (20-50-μs intervals), andstored using Digidata 1200 B interface and Pclamp8.0/Clampex software(Axon Instruments, Union City, Calif.). The pipettes are back-filledwith internal solution containing CsCl (110 mM), MgCl₂ (3 mM), EGTA (3mM), HEPES (40 mM), Mg-ATP (4 mM), Na₂GTP (0.5 mM), and adjusted to pH7.2 with CsOH. The pipette resistance ranges from 2 to 3 MOhm and iscompensated by 75-80% by the built-in electronic circuitry.

Currents are elicited by stepping from a holding potential of −90 mV to0 mV for 20 ms every 10 sec. At the −90 mV membrane voltage a proportionof channels is in the inactivated state, and thus contact with a blockerwould involve interaction with both resting and inactivated channels.This protocol is used as a first tier screen. For dissection of twocomponents of inhibition (resting block with the apparent dissociationconstant K_(r) and inactivated state block with K_(i)), steady-stateinactivation curves are collected using a double-pulse protocol.Three-second long depolarizing pre-pulse incrementing in 10 mV steps isfollowed by a 10 ms test pulse to 0 mV.

Stock solutions of each test compound are prepared using DMSO. Serialdilutions to desired concentrations are done with bath solution;concentration of DMSO in final solutions is 0.1%. Drugs are applied bygravity flow using a plane multi-barrel array shooter positioned ˜1 mmapart from the cell.

All curve fittings can be carried out using Origin software (version5.0, Microcal). A Hill equation is used to fit theconcentration-response curves and to determine IC₅₀ values. A Boltzmanequation is used to fit inactivation curves, returning half-inactivationvoltage, V_(0.5), slope p and the amplitude of current at the mostnegative voltage where eventually all channels are in the resting state.These parameters are used to calculate the apparent dissociationconstants: K_(r)=((Ab/Ac)/(1−(Ab/Ac))*[b]) where [b] is the drugconcentration, Ac is the maximum test current amplitude in controlconditions and Ab is the maximum test current amplitude in the presenceof a blocker; K_(i)=[b]/((exp(−(dx/p))*(1+([b]/K_(r)))−1) where dx isthe difference between half-inactivation voltage V_(0.5) in the presenceand absence of drug and p is the slope.

In Vivo Pharmacology

The compounds of the present invention can be tested for in vivoanticonvulsant activity after i.v., p.o., or i.p. injection using any ofa number of anticonvulsant tests in mice, including the maximumelectroshock seizure test (MES). Maximum electroshock seizures areinduced in male NSA mice weighing between 15-20 g and in maleSprague-Dawley rats weighing between 200-225 g by application of current(for mice: 50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration,D.C.; for rats: 99 mA, 125 pulses/sec, 0.8 msec pulse width, 2 secduration, D.C.) using a Ugo Basile ECT device (Model 7801). Mice arerestrained by gripping the loose skin on their dorsal surface andsaline-coated corneal electrodes are held lightly against the twocorneae. Rats are allowed free movement on the bench top and ear-clipelectrodes are used. Current is applied and animals are observed for aperiod of up to 30 seconds for the occurrence of a tonic hindlimbextensor response. A tonic seizure is defined as a hindlimb extension inexcess of 90 degrees from the plane of the body. Results can be treatedin a quantal manner.

The compounds can be tested for their antinociceptive activity in theformalin model as described in Hunskaar, S., O. B. Fasmer, and K. Hole,J. Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice(20-30 g; Harlan, San Diego, Calif.) can be used in all experiments.Food is withdrawn on the day of experiment. Mice are placed inPlexiglass jars for at least 1 hour to acclimate to the environment.Following the acclimation period mice are weighed and given either thecompound of interest administered i.p. or p.o., or the appropriatevolume of vehicle (10% Tween-80) as control. Fifteen minutes after thei.p. dosing, and 30 minutes after the p.o. dosing mice are injected withformalin (20 μL of 5% formaldehyde solution in saline) into the dorsalsurface of the right hind paw. Mice are transferred to the Plexiglassjars and monitored for the amount of time spent licking or biting theinjected paw. Periods of licking and biting are recorded in 5-minuteintervals for 1 hour after the formalin injection. All experiments aredone in a blinded manner during the light cycle. The early phase of theformalin response is measured as licking/biting between 0-5 minutes, andthe late phase is measured from 15-50 minutes. Differences betweenvehicle and drug treated groups can be analyzed by one-way analysis ofvariance (ANOVA). A P value <0.05 is considered significant. Compoundsare considered to be efficacious for treating acute and chronic pain ifthey have activity in blocking both the early and second phase offormalin-induced paw-licking activity.

Compounds can be tested for their potential to treat chronic pain (i.e.,antiallodynic and antihyperalgesic activities) using the Chung model ofperipheral neuropathy (Kim and Chung, Pain 50: 355-363 (1992)). MaleSprague-Dawley rats weighing between 200-225 g are anesthetized withhalothane (1-3% in a mixture of 70% air and 30% oxygen), and their bodytemperature controlled during anesthesia through use of a homeothermicblanket. A 2-cm dorsal midline incision is then made at the L5 and L6level, and the para-vertebral muscle groups retracted bilaterally. L5and L6 spinal nerves are then exposed, isolated, and tightly ligatedwith 6-0 or 7-0 silk suture. A sham operation is performed exposing thecontralateral L5 and L6 spinal nerves, without ligating, as a negativecontrol.

Tactile Allodynia:

Sensitivity to non-noxious mechanical stimuli can be measured in animalsto assess tactile allodynia. Rats are transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A series of von Frey monofilaments are applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possesses a buckling weight of 9.1 gms (0.96 logvalue) and is applied up to five times to see if it elicits a withdrawalresponse. If the animal has a withdrawal response, then the nextlightest filament in the series would be applied up to five times todetermine if it also could elicit a response. This procedure is repeatedwith subsequent lesser filaments until there is no response and theidentity of the lightest filament that elicits a response is recorded.If the animal does not have a withdrawal response from the initial 9.1gms filament, then subsequent filaments of increased weight are applieduntil a filament elicits a response and the identity of this filament isrecorded. For each animal, three measurements are made at every timepoint to produce an average withdrawal threshold determination. Testscan be performed prior to, and at 1, 2, 4 and 24 hours post drugadministration.

Mechanical Hyperalgesia:

Sensitivity to noxious mechanical stimuli can be measured in animalsusing the paw pressure test to assess mechanical hyperalgesia. In rats,hind paw withdrawal thresholds (“PWT”), measured in grams, in responseto a noxious mechanical stimulus are determined using an analgesymeter(Model 7200, commercially available from Ugo Basile of Italy), asdescribed in Stein (Biochemistry & Behavior 31: 451-455 (1988)). Therat's paw is placed on a small platform, and weight is applied in agraded manner up to a maximum of 250 grams. The endpoint is taken as theweight at which the paw is completely withdrawn. PWT is determined oncefor each rat at each time point. PWT can be measured only in the injuredpaw, or in both the injured and non-injured paw. In one non-limitingembodiment, mechanical hyperalgesia associated with nerve injuty inducedpain (neuropathic pain) can be assessed in rats. Rats are tested priorto surgery to determine a baseline, or normal, PWT. Rats are testedagain 2 to 3 weeks post-surgery, prior to, and at different times after(e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWTfollowing drug administration indicates that the test compound reducesmechanical hyperalgesia.

Pharmaceutical Compositions

Although a compound of the present invention may be administered to amammal in the form of a raw chemical without any other componentspresent, the compound is preferably administered as part of apharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the present inventioninclude all compositions where a compound of the present invention iscombined with a pharmaceutically acceptable carrier. In a preferredembodiment, the compound is present in the composition in an amount thatis effective to achieve its intended therapeutic purpose. Whileindividual needs may vary, a determination of optimal ranges ofeffective amounts of each compound is within the skill of the art.Typically, the compounds may be administered to a mammal, e.g., a human,orally at a dose of from about 0.0025 to about 1500 mg per kg bodyweight of the mammal, or an equivalent amount of a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, per day to treat, preventor ameliorate the particular disorder. A useful oral dose of a compoundof the present invention administered to a mammal is from about 0.0025to about 50 mg per kg body weight of the mammal, or an equivalent amountof the pharmaceutically acceptable salt, prodrug, or solvate thereof.For intramuscular injection, the dose is typically about one-half of theoral dose.

A unit oral dose may comprise from about 0.01 to about 50 mg, andpreferably about 0.1 to about 10 mg, of the compound. The unit dose canbe administered one or more times daily, e.g., as one or more tablets orcapsules, each containing from about 0.01 to about 50 mg of thecompound, or an equivalent amount of a pharmaceutically acceptable salt,prodrug or solvate thereof.

A pharmaceutical composition of the present invention can beadministered to any animal that may experience the beneficial effects ofa compound of the present invention. Foremost among such animals aremammals, e.g., humans and companion animals, although the invention isnot intended to be so limited.

A pharmaceutical composition of the present invention can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, health, and weight of the recipient,condition or disorder to be treated, kind of concurrent treatment, ifany, frequency of treatment, and the nature of the effect desired.

In one embodiment, a pharmaceutical composition of the present inventioncan be administered orally and is formulated into tablets, dragees,capsules or an oral liquid preparation. In one embodiment, the oralformulation comprises extruded multiparticulates comprising the compoundof the invention.

Alternatively, a pharmaceutical composition of the present invention canbe administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present invention canbe administered by injection.

Alternatively, a pharmaceutical composition of the present invention canbe administered transdermally.

Alternatively, a pharmaceutical composition of the present invention canbe administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present invention canbe administered by the intravaginal route.

A pharmaceutical composition of the present invention can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present invention, such as a method for treating adisorder responsive to the blockade of calcium channels in an animal inneed thereof, can further comprise administering a second therapeuticagent to the animal in combination with a compound of the presentinvention. In one embodiment, the other therapeutic agent isadministered in an effective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

A compound of the present invention (i.e., the first therapeutic agent)and the second therapeutic agent can act additively or, in oneembodiment, synergistically. Alternatively, the second therapeutic agentcan be used to treat a disorder or condition that is different from thedisorder or condition for which the first therapeutic agent is beingadministered, and which disorder or condition may or may not be acondition or disorder as defined herein. In one embodiment, a compoundof the present invention is administered concurrently with a secondtherapeutic agent; for example, a single composition comprising both aneffective amount of a compound of any of Formulae I-VIII, and aneffective amount of the second therapeutic agent can be administered.Accordingly, the present invention further provides a pharmaceuticalcomposition comprising a combination of a compound of the presentinvention, the second therapeutic agent, and a pharmaceuticallyacceptable carrier. Alternatively, a first pharmaceutical compositioncomprising an effective amount of a compound of any of Formulae I-VIIIand a second pharmaceutical composition comprising an effective amountof the second therapeutic agent can be concurrently administered. Inanother embodiment, an effective amount of a compound of the presentinvention is administered prior or subsequent to administration of aneffective amount of the second therapeutic agent. In this embodiment,the compound of the present invention is administered while the secondtherapeutic agent exerts its therapeutic effect, or the secondtherapeutic agent is administered while the compound of the presentinvention exerts its therapeutic effect for treating a disorder orcondition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof.Examples of other suitable non-opioid analgesics include the following,non limiting, chemical classes of analgesic, antipyretic, nonsteroidalantiinflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; paraaminophennol derivatives including acetaminophen and phenacetin; indoleand indene acetic acids, including indomethacin, sulindac, and etodolac;heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac;anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R.Hanson, Analgesic, Antipyretic and Anti Inflammatory Drugs in Remington:The Science and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed.19th ed. 1995) which are hereby incorporated by reference in theirentireties. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, and cisplatin.

Therapeutic agents useful for treating an addictive disorder include,but are not limited to, methadone, desipramine, amantadine, fluoxetine,buprenorphine, an opiate agonist, 3-phenoxypyridine, or a serotoninantagonist.

Examples of useful therapeutic agents for treating Parkinson's diseaseand parkinsonism include, but are not limited to, carbidopa/levodopa,pergolide, bromocriptine, ropinirole, pramipexole, entacapone,tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride.

Examples of useful therapeutic agents for treating anxiety include, butare not limited to, benzodiazepines, such as alprazolam, brotizolam,chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam,diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam,midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam,temazepam, and triazolam; non-benzodiazepine agents, such as buspirone,gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon;tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital,butabarbital, butalbital, mephobarbital, methohexital, pentobarbital,phenobarbital, secobarbital, and thiopental; and propanediol carbamates,such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating epilepsy or seizureinclude, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, gamma-vinyl GABA, acetazolamide,and felbamate.

Examples of useful therapeutic agents for treating stroke include, butare not limited to, anticoagulants such as heparin, agents that break upclots such as streptokinase or tissue plasminogen activator, agents thatreduce swelling such as mannitol or corticosteroids, and acetylsalicylicacid.

Examples of useful therapeutic agents for treating a pruritic conditioninclude, but are not limited to, naltrexone; nalmefene; danazol;tricyclics such as amitriptyline, imipramine, and doxepin;antidepressants such as those given below; menthol; camphor; phenol;pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating psychosis include,but are not limited to, phenothiazines such as chlorpromazinehydrochloride, mesoridazine besylate, and thoridazine hydrochloride;thioxanthenes such as chloroprothixene and thiothixene hydrochloride;clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate;haloperidol; haloperidol decanoate; loxapine succinate; molindonehydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating ALS include, but arenot limited to, baclofen, neurotrophic factors, riluzole, tizanidine,benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating cognitive disordersinclude, but are not limited to, agents for treating or preventingdementia such as tacrine; donepezil; ibuprofen; antipsychotic drugs suchas thioridazine and haloperidol; and antidepressant drugs such as thosegiven below.

Examples of useful therapeutic agents for treating a migraine include,but are not limited to, sumatriptan; methysergide; ergotamine; caffeine;and beta-blockers such as propranolol, verapamil, and divalproex.

Examples of useful therapeutic agents for treating vomiting include, butare not limited to, 5-HT3 receptor antagonists such as ondansetron,dolasetron, granisetron, and tropisetron; dopamine receptor antagonistssuch as prochlorperazine, thiethylperazine, chlorpromazine,metoclopramide, and domperidone; glucocorticoids such as dexamethasone;and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating dyskinesia include,but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating depression include,but are not limited to, tricyclic antidepressants such as amitryptyline,amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine,maprotiline, nefazadone, nortriptyline, protriptyline, trazodone,trimipramine, and venlafaxine; selective serotonin reuptake inhibitorssuch as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine,and setraline; monoamine oxidase inhibitors such as isocarboxazid,pargyline, phenelzine, and tranylcypromine; and psychostimulants such asdextroamphetamine and methylphenidate.

A pharmaceutical composition of the present invention is preferablymanufactured in a manner which itself will be known in view of theinstant disclosure, for example, by means of conventional mixing,granulating, dragee-making, dissolving, extrusion, or lyophilizingprocesses. Thus, pharmaceutical compositions for oral use can beobtained by combining the active compound with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate can be used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which may bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers may be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound may be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the present invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the invention.

EXAMPLES Example 1N-Isopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (6)

NaB(OAc)₃H (14 g, 66 mmol, Aldrich) was added to a mixture of compound 1(10 g, 50 mmol, Aldrich), compound 2 (3 g, 52.5 mmol, Aldrich),molecular sieves (4 Å beads, 20 g, Aldrich) in DCE (200 mL) at 0° C. Theresulting mixture was stirred at room temperature for 24 hours. Thereaction mixture was quenched with MeOH (2 mL), filtered over celite,washed with water, 2N NaOH and concentrated under vacuum to afford crudecompound 3 as a colorless oil. Compound 4 (12 g, 49 mmol, Aldrich) wasadded to a mixture of the above crude compound 3, TEA (10 mL) and DCM(10 mL) at room temperature. The resulting mixture was heated andstirred at 37° C. for 2 days. The reaction mixture was then cooled toroom temperature, washed with water (10 mL), brine, concentrated andpurified by column (silica gel, EtOAc/hexanes 3/7) to obtain compound 5as a sticky oil (10 g, yield 45% in two steps), which was dissolved in100 mL of 1,4-dioxane. HCl (10 mL, concentrated aq.) was added to the1,4-dioxane solution at room temperature. The resulting mixture wasstirred at room temperature for 48 hours, and concentrated under vacuum.The residue was washed with ethyl ether, and dried to obtain the titlecompound 6 as HCl-salt, which was suspended in EtOAc, and neutralizedwith 1N NaOH aq, concentrated and dried under vacuum to give compound 6as colorless oil (5 g, yield 65%).

Example 22-[4-[Isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}propionicacid ethyl ester (8a)2-{4-[Isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}-2-methylpropionicacid ethyl ester (8b){-4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}aceticacid 4-chlorophenyl ester (8c)

General procedure for compounds 8a-c: A mixture of compound 6 or 6a (200mg, 1.0 eq.) and 1.0 eq of the corresponding compound 7 (7a-c, Aldrich),2 eq. of K₂CO₃, benzyltriethylammonium chloride (TEBAC, 0.1 eq., ACROS)and KI (0.1 eq.) in 3 mL of CH₃CN was shaken at 40° C. over a weekend.The reaction mixture was washed with water (5 mL), extracted with DCM(15 mL), the layers were separated, the solvent was evaporated, and theresidue was purified by column (Silica gel, EtOAc/Hexane 3/7 to 1/1) toget the title compounds 8a-c.

2-{4-[Isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-propionicacid ethyl ester (8a, colorless oil, yield 66%). ¹H NMR (400 MHz,CD₃OD): δ 8.13 (s, 1H), 8.05 (d, 1H, 8.1 Hz), 7.78 (d, 1H, 7.9 Hz), 7.63(dd, 1H, 8.1, 7.9 Hz), 4.16 (q, 1H, 7.2 Hz), 3.73-3.81 (m, 1H),3.26-3.31 (m, 1H), 2.88-2.96 (m, 2H), 2.31-2.37 (m, 1H), 2.21-2.27 (m,1H), 1.94-2.08 (m, 2H), 1.51-1.58 (m, 2H), 1.31 (d, 6H, 6.8 Hz), 1.27(t, 3H, 5.9 Hz); LC: 100%; MS: m/z=451 (M+1).

2-{-4-[Isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-2-methyl-propionicacid ethyl ester (8b, colorless oil, yield 50%): ¹H NMR (400 MHz,CD₃OD): δ 8.13 (s, 1H), 8.06 (d, 1H, 7.9 Hz), 7.78 (d, 1H, 7.9 Hz), 7.63(dd, 1H, 7.7, 7.9 Hz), 4.17 (q, 1H, 7.2 Hz), 3.72-3.78 (m, 1H),3.28-3.35 (m, 1H), 2.96-3.01 (m, 2H), 2.11-2.16 (m, 2H), 1.92-2.01 (m,2H), 1.52-1.56 (m, 2H), 1.32 (d, 6H, 6.8 Hz), 1.28 (s, 6H), 1.27 (t, 3H,7.1 Hz); LC: 100%; MS: m/z=465 (M+1).

{4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-aceticacid 4-chloro-phenyl ester (8c, pale yellow solid, yield 85%): ¹H NMR(400 MHz, CD₃OD): δ 8.12 (s, 1H), 8.05 (d, 1H, 7.9 Hz), 7.81 (d, 1H, 7.9Hz), 7.69 (dd, 1H, 7.9, 7.9 Hz), 7.24 (d, 2H, 8.9 Hz), 6.88 (d, 2H, 8.9Hz), 4.67-4.72 (m, 3H), 4.07-4.12 (m, 2H), 3.02-3.11 (m, 1H), 2.52-2.61(m, 1H), 1.86-1.91 (m, 1H), 1.68-1.78 (m, 3H), 1.52-1.56 (m, 1H),0.69-0.94 (m, 4H); LC: 100%; MS: m/z=517 (M+1).

Example 32-{4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}benzoicacid methyl ester (10a)4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-3′-carboxylicacid ethyl ester (10b)3-{-4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}-5-fluorobenzoicacid ethyl ester (10c)4-{-4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}benzoicacid ethyl ester (10d)N-[1-(3,5-Bis-(trifluoromethyl)phenyl)piperidin-1-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide(10e)

General procedure for compounds 10a-e: A mixture 0.2 g of compound 6a(1.0 eq., Oakwood), compound 9 (1.0 eq.), and 0.3 g of K₂CO₃ in 1 mL ofDMSO was heated and shaken at 90° C. for 36 hours. After cooling to roomtemperature, the reaction mixture was diluted with CHCl₃, washed withwater, evaporated and purified by column (silica gel, EtOAc/hexanes 3/7to 1/1) to give the title compounds 10a-e.

2-{4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-benzoicacid methyl ester (10a, stick oil, yield 56%). ¹H NMR (400 MHz, CD₃OD):δ 8.18 (s, 1H), 8.08 (d, 1H, 7.9 Hz), 7.88 (d, 1H, 7.9 Hz), 7.74 (dd,1H, 1.5 & 7.9 Hz), 7.69 (dd, 1H, 7.9 & 7.9 Hz), 7.38-7.42 (m, 1H), 6.97(m, 2H), 4.67-4.72 (m, 3H), 3.97-4.05 (m, 2H), 3.87 (s, 3H), 3.32-3.38(m, 2H), 2.78-2.82 (m, 2H), 2.12-2.22 (m, 2H), 2.02-2.06 (m, 1H),1.6-1.65 (m, 2H), 0.62-1.05 (m, 4H); LC: 100%; MS: m/z=483 (M+1).

4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-carboxylicacid ethyl ester (10b, stick oil, yield 85%). ¹H NMR (400 MHz, CD₃OD): δ8.25 (dd, 1H, 1.9 & 4.8 Hz), 8.16 (s, 1H), 8.09 (d, 1H, 7.9 Hz), 7.97(dd, 1H, 1.9 & 7.4 Hz), 7.86 (d, 1H, 7.9 Hz), 7.69 (dd, 1H, 7.9 & 7.9Hz), 6.75 (dd, 21-1, 4.8 & 7.6 Hz), 4.32 (q, 2H, 7.0 Hz), 4.05-4.13 (m,1H), 3.86-3.91 (m, 2H), 2.9-2.96 (m, 2H), 1.97-2.06 (m, 3H), 1.6-1.65(m, 2H), 0.96-1.01 (m, 2H), 0.76-0.81 (m, 2H); LC: 100%; MS: m/z=498(M+1).

3-{-4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-5-fluoro-benzoicacid ethyl ester (10c, stick oil, yield 45%). ¹H NMR (400 MHz, CD₃OD): δ8.22 (d, 1H, 7.9 Hz), 8.16 (s, 1H), 8.03 (dd, 1H, 0.65 & 7.9 Hz), 7.87(dd, 1H, 7.9 & 8.4 Hz), 7.48 (s, 1H), 7.18 (d, 1H, 8.9 Hz), 7.01-7.05(m, 1H), 4.37 (q, 2H, 7.0 Hz), 4.07-4.15 (m, 1H), 3.79-3.84 (m, 2H),2.93-2.99 (m, 2H), 2.06-2.17 (m, 3H), 1.67-1.73 (m, 2H), 1.39 (t, 3H,7.2 Hz), 0.95-0.97 (m, 2H), 0.8-0.84 (m, 2H); LC: 100%; MS: m/z=515(M+1).

4-{-4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-benzoicacid ethyl ester (10d, white solid, yield 75%). ¹H NMR (400 MHz, CD₃OD):δ 8.22 (d, 1H, 7.9 Hz), 8.18 (s, 1H), 8.03 (d, 1H, 8.3 Hz), 7.92 (d, 2H,8.9 Hz), 7.87 (dd, 1H, 7.8 & 7.9 Hz), 7.08 (d, 2H, 8.9 Hz), 4.33 (q, 2H,7.2 Hz), 4.13-4.21 (m, 1H), 3.92-3.98 (m, 2H), 3.02-3.09 (m, 2H),2.06-2.16 (m, 3H), 1.68-1.74 (m, 2H), 1.38 (t, 3H, 7.2 Hz), 0.94-0.97(m, 2H), 0.79-0.83 (m, 2H); LC: 100%; MS: m/z=497 (M+1).

N-[1-(3,5-Bis-trifluoromethyl-phenyl)-piperidin-4-yl]-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide(10e, white solid, yield 90%): ¹H NMR (400 MHz, CD₃OD): δ 8.16 (s, 1H),8.09 (d, 1H, 7.9 Hz), 7.88 (d, 1H, 7.9 Hz), 7.71 (dd, 1H, 7.9 & 7.9 Hz),7.32 (s, 1H), 7.28 (s, 2H), 4.05-4.13 (m, 1H), 3.76-3.82 (m, 2H),2.87-2.94 (m, 2H), 1.99-2.04 (m, 1H), 1.71-1.77 (m, 2H), 0.97-1.01 (m,2H), 0.79-0.84 (m, 2H); LC: 100%; MS: m/z=561 (M+1).

Example 4N-(2-{-4-[Cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]piperidin-1-yl}ethyl)-4-fluorobenzamide(14a)N-(2-{4-[Cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]piperidin-1-yl}ethyl)-3,5-bis(trifluoromethyl)phenylbenzamide(14b)

General procedure for the preparation of compounds 14a and 14b: Amixture of compound 6a (0.5 g), compound 11 (160 mg), K₂CO₃ (400 mg),TEBAC (50 mg) and CH₃CN (4 mL) was shaken at 60° C. for 48 hours. Thereaction mixture was cooled to room temperature, washed with water (4mL), extracted with CHCl₃ (2×10 mL), concentrated and purified by column(Silica gel, EtOAc/MeOH/NH₄OH 100/10/1) to give compound 12 as stickyoil (yield 60%). Compound 13 was added to a solution of compound 12 (100mg, 1.0 eq.) and TEA (2.0 eq.) in DCM (4 mL) at 0° C., and the resultingmixture was stirred at 0° C. to room temperature over night. The mixturewas washed with water, separated and purified by column (silica gel,EtOAc/Hexane 1/1) to give the title compounds 14a and 14b.

N-[1-(2-Amino-ethyl)-piperidin-4-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide(12): ¹H NMR (400 MHz, CD₃OD): δ 8.24 (d, 1H, 7.9 Hz), 8.18 (s, 1H),8.04 (d, 1H, 7.9 Hz), 7.88 (dd, 1H, 7.8 & 7.9 Hz), 4.24-4.31 (m, 1H),3.68-3.73 (m, 2H), 3.42-3.47 (m, 4H), 3.19-3.26 (m, 2H), 2.45-2.55 (m,2H), 2.06-2.11 (m, 1H), 1.87-1.92 (m, 2H), 0.95-0.98 (m, 2H), 0.85-0.89(m, 2H); LC: 100%; MS: m/z=392 (M+1).

N-(2-{4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-ethyl)-4-fluoro-benzamide (14a, sticksolid, yield 50%): ¹H NMR (400 MHz, CD₃OD): δ 8.13 (s, 1H), 8.06 (d, 1H,7.9 Hz), 7.85 (d, 1H, 7.9 Hz), 7.77 (dd, 2H, 5.2 & 8.9 Hz), 7.68 (dd,1H, 7.8 & 7.9 Hz), 7.11 (dd, 2H, 8.5 & 8.9 Hz), 6.64 (br, 1H, NH),3.83-3.91 (m, 1H), 3.49-3.53 (m, 2H), 2.94-2.99 (m, 2H), 2.57-2.61 (m,2H), 2.07-2.13 (m, 2H), 1.94-2.02 (m, 3H), 1.55-1.61 (m, 2H), 0.96-0.99(m, 2H), 0.78-0.81 (m, 2H); LC: 100%; MS: m/z=514 (M+1).

N-(2-{4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-ethyl)-3,5-bis-trifluoromethylbenzamide(14b, white solid, yield 55%): ¹H NMR (400 MHz, CD₃OD): δ 8.21 (s, 2H),8.14 (s, 1H), 8.07 (d, 1H, 7.9 Hz), 8.0 (s, 1H), 7.86 (d, 1H, 7.9 Hz),7.69 (dd, 1H, 7.8 & 7.9 Hz), 6.94 (br, 1H, NH), 3.88-3.94 (m, 1H),3.52-3.58 (m, 2H), 2.94-3.01 (m, 2H), 2.58-2.64 (m, 2H), 2.10-2.18 (m,2H), 1.92-2.01 (m, 3H), 1.56-1.62 (m, 2H), 0.95-1.01 (m, 2H), 0.76-0.81(m, 2H); LC: 100%; MS: m/z=632 (M+1).

Example 5N-Isopropyl-N-[1-(3-oxo-3-piperidin-1-yl-propyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide(18)

A mixture of compounds 6 (2 g, 5.2 mmol), 15 (0.62 g, 1.2 eq, Aldrich),and TEA (1 mL) in EtOH was shaken at 80° C. for 16 hours. After coolingto room temperature, the solvent was removed, and the residue wassuspended in water (10 mL), extracted with EtOAc (3×20 mL), concentratedand purified by column (silica gel, EtOAc/hexane 1/1) to give compound16 as colorless oil (0.5 g, 20%).

Me₃Al (2N in hexane, 0.5 mL) was added to a solution of piperidine (17)(0.4 mmol) in 2 mL of dry DCM at room temperature under argon. Theresulting mixture was shaken at it for 30 minutes and then a solution ofcompound 16 (150 mg, 0.3 mmol in 1 mL of DCM) was added to it. Thereaction mixture was shaken at 40° C. for 3 days. After cooling to roomtemperature, the reaction mixture was diluted with DCM/MeOH (10 mL/0.2mL), and washed with NaOH (2N, 2 mL). The organic layer was washed withbrine, concentrated and purified by column (EtOAc/hexanes 1/1) to givethe title compound 18 as free base, which was converted to its HCl-saltby treating with HCl (1 N aqueous) and drying under vacuum: ¹HNMR(HCl-salt, 400 MHz, CD₃OD): δ 8.18-8.22 (m, 1H), 8.15 (s, 1H),7.97-8.01 (m, 1H), 7.83-7.87 (m, 1H), 3.91-3.95 (m, 1H), 3.66-3.76 (m,3H), 3.49-3.59 (m, 4H), 3.39-3.43 (m, 2H), 3.17-3.23 (m, 2H), 2.93-2.97(m, 2H), 2.65-2.72 (m, 2H), 1.9-1.98 (m, 2H), 1.55-1.75 (m, 6H),1.19-1.24 (m, 6H).

Example 6N-(2-Chloro-4-fluorophenyl)-2-{-4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-isobutyramide(21a)2-{-4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-N-(4-fluoro-phenyl)-isobutyramide(21b)

Compound 19 was prepared according to the procedure described in Example2.

General procedure for the synthesis of compounds 21a and 21b: Me₃Al (2Nin hexane, 0.5 mL) was added to a solution of compound 20a (or 20b, 0.6mmol) in 2 mL of dry DCM at room temperature under argon. The resultingmixture was shaken at room temperature for 30 minutes and then asolution of compound 19 (0.5 mmol) in 2 mL of DCM was added to it. Thereaction mixture was shaken at 40° C. for 3 days. After cooling to roomtemperature, the mixture was quenched with MeOH (0.1 mL) and washed withNaOH (1N, 2 mL). The organic layer was separated, concentrated andpurified by column (silica gel, EtOAc/hexane 1/1) to give the desiredproduct.

N-(2-Chloro-4-fluoro-phenyl)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]piperidin-1-yl}-isobutyramide(21a) (white solid, yield 15%): ¹H NMR (400 MHz, CDCl₃): δ 9.98 (s, 1H,NH), 8.46 (dd, 1H, 5.7 & 9.2 Hz), 8.14 (s, 1H), 7.87 (d, 1H, 7.9 Hz),7.66-7.71 (m, 1H), 7.11 (dd, 1H, 2.8 & 8.1 Hz), 6.97-7.02 (m, 1H),3.86-3.93 (m, 1H), 2.86-2.91 (m, 2H), 2.25-2.31 (m, 2H), 1.99-2.11 (m,3H), 1.64-1.68 (m, 2H), 1.28 (s, 6H), 1.0-1.03 (m, 2H), 0.79-0.82 (m,2H); LC: 100%; MS: m/z=562 (M+1).

2-{-4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-N-(4-fluoro-phenyl)-isobutyramide(21b) (brown solid): ¹H NMR (400 MHz, CDCl₃): δ 9.18 (s, 1H, NH), 8.14(s, 1H), 8.06 (d, 1H, 7.9 Hz), 7.85 (d, 1H, 7.8 Hz), 7.65-7.61 (m, 1H),7.44-7.48 (m, 2H), 6.99-7.03 (m, 2H), 3.81-3.87 (m, 1H), 2.86-2.91 (m,2H), 2.25-2.31 (m, 2H), 1.99-2.11 (m, 3H), 1.67-1.72 (m, 2H), 1.28 (s,6H), 1.0-1.03 (m, 2H), 0.79-0.82 (m, 2H); LC: 100%; MS: m/z=528 (M+1).

Example 73-{4-[Isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}-N-tert-butyl-butyramide(25)

3-{4-[Isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}-N-tert-butyl-butyramide(25) was prepared as follows. DIC (2.4 g, 1.05 eq.) was added to amixture of compound 22 (3 g, 18 mmol, 1.0 eq., Aldrich), HOBt (100 mg),and compound 23 (20 mmol) at 0° C. The reaction mixture was warmed toroom temperature over night and the solid was filtered off. The organiclayer was purified by column to give compound 24 as colorless oil (1.6g).

A mixture of compound 24 (0.2 g, 0.9 mmol), compound 6 (0.3 g, 0.86mmol), K₂CO₃ (0.5 g, 3.6 mmol) and TEA (0.2 mL) in 4 mL of CH₃CN wasshaken at 40° C. for 24 hours. After cooling to room temperature, water(5 mL) and DCM (20 mL) were added to the mixture. The organic phase wasseparated, concentrated and purified by column to give the titlecompound 25 as a white solid (200 mg, yield 45%): ¹H NMR (400 MHz,CDCl₃): δ 8.13 (s, 1H), 8.07 (d, 1H, 7.5 Hz), 7.78-7.82 (m, 1H),7.62-7.66 (m, 1H), 6.94 (br, 1H, NH), 3.8-3.86 (m, 1H), 3.05-3.21 (m,3H), 2.9-2.97 (m, 2H), 2.76-2.79 (m, 1H), 2.1-2.28 (m, 4H), 1.62-1.83(m, 5H), 1.2-1.24 (m, 6H), 0.94-0.96 (m, 9H); LC: 100%; MS: m/z=492(M+1).

Example 8N-Isopropyl-N-[1-(2-oxo-1-phenyl-pyrrolidin-3-yl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide(27a)2-{4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]piperidin-1-yl}-N-phenyl-propionamide(27b)

Compounds 27a and 27b were prepared according to the procedure describedin Example 7 using compounds 26a (Fluka) and 26b (Aldrich) as startingmaterials, respectively.

N-Isopropyl-N-[1-(2-oxo-1-phenyl-pyrrolidin-3-yl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide(27a) (white solid): ¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 1H), 8.07 (d,1H, 7.9 Hz), 7.78-8.01 (m, 1H), 7.6-7.67 (m, 3H), 7.35-7.38 (m, 2H),7.14-7.18 (m, 1H), 3.73-3.83 (m, 3H), 3.61-3.66 (m, 1H), 3.32-3.40 (m,1H), 3.06-3.11 (m, 1H), 2.92-2.97 (m, 1H), 2.75-2.82 (m, 1H), 2.38-2.45(m, 1H), 2.25-2.35 (m, 1H), 2.07-2.15 (m, 3H), 1.55-1.65 (m, 2H),1.28-1.34 (m, 6H).

2-{-4-[Cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]piperidin-1-yl}-N-phenyl-propionamide(27b) (white solid): ¹H NMR (400 MHz, CDCl₃): δ 9.13 (s, 1H), 8.12 (s,1H), 8.07 (d, 1H, 7.5 Hz), 7.78-7.82 (m, 1H), 7.67-7.71 (m, 1H),7.51-7.54 (m, 2H), 7.31-7.35 (m, 2H), 7.08-7.12 (m, 1H), 3.84-3.9 (m,1H), 3.2-3.24 (m, 1H), 2.82-2.91 (m, 2H), 2.46-2.52 (m, 1H), 2.22-2.28(m, 1H), 1.94-2.08 (m, 3H), 1.64-1.7 (m, 2H), 1.28-1.32 (m, 3H),0.99-1.02 (m, 2H), 0.82-0.86 (m, 2H); LC: 100%; MS: m/z=496 (M+1).

Example 9N-[1-(2-Azepan-1-yl-2-oxo-ethyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide(31a)N-Isopropyl-N-[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide(31b)N-Cycloheptyl-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide(31c)N-Bicyclo[2.2.1]hept-2-yl-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide(31d)2-{4-[Isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-N-(tetrahydrofuran-3-yl)-acetamide(31e)N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide(31f)

General procedure for preparing compounds 31a-f: A mixture of compound 6(2 g, 5.7 mmol), compound 28 (1.3 g, 1.0 eq., Aldrich) and K₂CO₃ (2 g,15 mmol) in 100 mL of CH₃CN was stirred at room temperature under N₂ for4 days. The reaction mixture was participated between water (50 mL) andDCM (200 mL). The organic layer was separated, evaporated and purifiedby column to give compound 29 as a white solid (2.5 g).

Me₃Al (2N in hexane, 0.5 mL, 1.0 mmol, Aldrich) was added to a solutionof the corresponding amine (30a-f, 0.5 mmol) in dry DCM (2 mL) at roomtemperature over 5 minutes. The reaction mixture was shaken at roomtemperature for 30 minutes and then compound 29 (150 mg, 0.34 mmol) wasadded. The mixture was shaken at 40° C. for 48 hours. After cooling toroom temperature, the reaction mixture was diluted with DCM (10 mL),washed with NaOH (2N, 2 mL) and brine (2 mL), concentrated and purifiedby column (silica gel, EtOAc/hexane 1/1) to give the title compounds31a-f.

N-[1-(2-Azepan-1-yl-2-oxo-ethyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide(31a) (white solid, HCl-salt): ¹H NMR (400 MHz, CD₃OD): δ 8.12-8.22 (m,2H), 7.97-8.01 (m, 1H), 7.83-7.87 (m, 1H), 4.22 (s, 2H), 3.92-3.96 (m,1H), 3.58-3.72 (m, 4H), 3.42-3.52 (m, 3H), 3.16-3.24 (m, 2H), 2.7-2.8(m, 2H), 1.94-2.0 (m, 2H), 1.74-1.83 (m, 4H), 1.6-1.66 (m, 4H),1.18-1.22 (m, 6H).

N-Isopropyl-N-[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide(31b) (white solid, HCl-salt): ¹H NMR (400 MHz, CD₃OD): δ 8.22-8.31 (m,2H), 8.06-8.09 (m, 1H), 7.9-7.94 (m, 1H), 4.22 (s, 2H), 4.0-4.05 (m,1H), 3.75-3.82 (m, 3H), 3.5-3.6 (m, 4H), 3.25-3.31 (m, 2H), 2.78-2.86(m, 2H), 2.0-2.12 (m, 6H), 1.24-1.3 (m, 6H).

N-Cycloheptyl-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide(31c) (HCl-salt, white solid): ¹H NMR (400 MHz, CD₃OD): δ 8.16-8.22 (m,2H), 7.98-8.01 (m, 1H), 7.82-7.86 (m, 1H), 3.6-3.88 (m, 7H), 3.12-3.2(m, 2H), 2.68-2.76 (m, 2H), 1.9-1.98 (m, 4H), 1.5-1.7 (m, 10H),1.18-1.22 (m, 6H).

N-Bicyclo[2.2.1]hept-2-yl-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide(31d) (HCl-salt, white solid): ¹H NMR (400 MHz, CD₃OD): δ 8.16-8.22 (m,2H), 7.98-8.01 (m, 1H), 7.82-7.86 (m, 1H), 3.6-3.88 (m, 7H), 3.12-3.2(m, 2H), 2.68-2.76 (m, 2H), 2.2-2.3 (m, 2H), 1.93-1.98 (m, 2H),1.74-1.78 (m, 1H), 1.18-1.62 (m, 13H).

2-{-4-[Isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-N-(tetrahydrofuran-3-yl)-acetamide(31e) (HCl-salt, white solid): ¹H NMR (400 MHz, CD₃OD): δ 8.16-8.22 (m,2H), 7.98-8.01 (m, 1H), 7.82-7.86 (m, 1H), 4.43-4.47 (m, 1H), 3.8-3.95(m, 6H), 3.68-3.7 (m, 4H), 3.15-3.25 (m, 2H), 2.7-2.8 (m, 2H), 2.23-2.31(m, 1H), 1.83-1.98 (m, 3H), 1.15-1.22 (m, 6H).

N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide(31f) (white solid): ¹H NMR (400 MHz, CDCl₃): δ 9.2 (s, 1H, NH), 8.14(s, 1H), 8.07 (d, 1H, 7.9 Hz), 7.78-8.01 (m, 1H), 7.7 (d, 1H, 1.9 Hz),7.64-7.68 (m, 3H), 6.99-7.02 (m, 2H), 3.83-3.87 (m, 1H), 3.0-3.26 (m,5H), 2.32-2.44 (m, 4H), 1.65-1.75 (m, 2H), 1.22-1.3 (m, 6H).

Example 10

Compounds of the invention have been tested in the calcium mobilizationand/or electrophysiological assay for N-type calcium channel blockingactivity, which are described in detail above. Some compounds describedhave also been tested in the calcium mobilization assay for L-typecalcium channel blocking activity, which is described in detail above.Representative values are presented in TABLE 2.

TABLE 2 Evaluation of the tested compounds as N-type calcium channel(NTCC) blockers and L-type calcium channel (LTCC) blockers after acalcium mobilization in vitro assay NTCC LTCC IC₅₀ IC₅₀ COMPOUND (μM)(μM) 2-[4-[Isopropyl-(3-trifluoromethyl- 1.01 NDbenzenesulfonyl)amino]piperidin-1-yl}propionic acid ethyl ester (8a)2-{4-[Isopropyl-(3-trifluoromethyl- 0.62 >20benzenesulfonyl)amino]piperidin-1-yl}-2- methylpropionic acid ethylester (8b) {4-[Cyclopropyl-(3-trifluoromethyl- 0.60 >20benzenesulfonyl)amino]piperidin-1-yl}acetic acid 4-chlorophenyl ester(8c) 2-{4-[Cyclopropyl-(3-trifluoromethyl- 0.90 >20benzenesulfonyl)amino]piperidin-1-yl}benzoic acid methyl ester (10a)4-[Cyclopropyl-(3-trifluoromethyl- 1.44 NDbenzenesulfonyl)amino]-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-3′-carboxylic acid ethyl ester (10b)3-{4-[Cyclopropyl-(3-trifluoromethyl- 1.07 NDbenzenesulfonyl)amino]piperidin-1-yl}-5- fluorobenzoic acid ethyl ester(10c) 4-{4-[Cyclopropyl-(3-trifluoromethyl- 1.31 NDbenzenesulfonyl)amino]piperidin-1-yl}benzoic acid ethyl ester (10d)N-[1-(3,5-Bis-(trifluoromethyl)phenyl)piperidin-1- 6.27 NDyl]-N-cyclopropyl-3- trifluoromethylbenzenesulfonamide (10e)N-(2-{4-[Cyclopropyl-(3- 0.38 6.74trifluoromethylbenzenesulfonyl)amino]piperidin-1-yl}ethyl)-4-fluorobenzamide (14a)N-(2-{4-[Cyclopropyl-(3-trifluoromethyl- 1.13 NDbenzenesulfonyl)amino]piperidin-1-yl}ethyl)-3,5-bis(trifluoromethyl)phenylbenzamide (14b)N-isopropyl-N-[1-(3-oxo-3-piperidin-1-yl-propyl)- 0.77 >20piperidin-4-yl]-3-trifluoromethyl- benzenesulfonamide (18)N-(2-Chloro-4-fluorophenyl)-2-{4-[cyclopropyl-(3- 1.60 NDtrifluoromethylbenzenesulfonyl)amino]-piperidin- 1-yl}-isobutyramide(21a) 2-{4-[Cyclopropyl-(3-trifluoromethyl- 0.60 >20benzenesulfonyl)-amino]-piperidin-1-yl}N-(4- fluorophenyl)-isobutyramide(21b) 3-{4-[Isopropyl-(3-trifluoromethyl- 0.24 8.45benzenesulfonyl)amino]piperidin-1-yl}-N-tert- butyl-isobutyramide (25)N-Isopropyl-N-[1-(2-oxo-1-phenyl-pyrrolidin-3-yl)- 0.55 >20piperidin-4-yl]-3-trifluoromethyl-benzene- sulfonamide (27a)2-{4-[Cyclopropyl-(3-trifluoromethyl- 0.39 >20benzenesulfonyl)-amino]piperidin-1-yl}-N-phenyl- propionamide (27b)N-[1-(2-Azepan-1-yl-2-oxo-ethyl)-piperidin-4-yl]- 0.30 >20N-isopropyl-3-trifluoromethyl-benzesulfonamide (31a)N-Isopropyl-N-[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)- 1.61 NDpiperidin-4-yl]-3-trifluoromethyl- benzenesulfonamide (31b)N-Cycloheptyl-2-{4-[isopropyl-(3-trifluoromethyl- 0.26 7.85benzenesulfonyl)-amino]-piperidin-1-yl}- acetamide (31c)N-Bicyclo[2.2.1]hept-2-yl-2-{4-[isopropyl-(3- 0.34 4.12trifluoromethyl-benzenesulfonyl)-amino]- piperidin-1-yl}-acetamide (31d)2-{4-[Isopropyl-(3-trifluoromethyl- 3.20 NDbenzenesulfonyl)-amino]-piperidin-1-yl}-N-(tetrahydrofuran-3-yl)-acetamide (31e)N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-2-{4- 0.58 >20[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide (31f) ND = not determined

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference herein in their entirety.

What is claimed is:
 1. A compound having the Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: R¹ and R² are each independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, halogen, alkoxy, haloalkoxy,cyano, nitro, amino, aminoalkyl, alkylamino, dialkylamino, hydroxy,carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, anddialkylaminocarbonyl; R³ is selected from the group consisting of alkyl,alkenyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl,3-tetrahydrofuranylalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cyanoalkyl,carboxyalkyl, and alkoxycarbonylalkyl; p is 1 or 2; q is 0, 1, 2, or 3;Z is selected from the group consisting of Z¹, Z², Z³, Z⁴, and Z⁵,wherein: Z¹ is—(CH₂)_(m)—NH—C(O)—R⁴; Z² is—CR⁵R⁶—(CH₂)_(n)—C(O)—O—R⁷; Z³ is—CR⁸R⁹—(CH₂)_(r)—R¹⁰; Z⁴ is—CR¹¹R¹²—(CH₂)_(s)—C(O)—NR¹³R¹⁴; and Z⁵ is aryl or heteroarylsubstituted with at least one of alkoxycarbonyl, haloalkyl, carboxy,aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl, wherein saidaryl or heteroaryl can be further optionally substituted; R⁴ is selectedfrom the group consisting of alkyl; phenyl optionally substituted withone or more substituents each independently selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy,hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, andhydroxyalkylamino; heteroaryl optionally substituted with one or moresubstituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, dialkylamino, andhydroxyalkylamino; and —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) areeach independently selected from the group consisting of hydrogen,alkyl, optionally substituted aryl, and optionally substitutedheteroaryl, provided that when R^(4b) is optionally substitutedheteroaryl, then R^(4a) is alkyl, optionally substituted aryl, oroptionally substituted heteroaryl; R⁵ and R⁶ are each independentlyhydrogen, alkyl, alkoxy, or phenyl optionally substituted with one ortwo substituents independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino; R⁷ is selectedfrom the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, and optionally substituted heteroarylalkyl;provided that when R⁷ is alkyl, then at least one of R⁵ or R⁶ is otherthan hydrogen; R⁸ and R⁹ are both hydrogen or together form ═O; providedthat when R⁸ and R⁹ together form ═O, then r is other than 0 (zero); R¹⁰is a 5-membered, N-containing heteroaryl or a 5-membered, partiallyunsaturated, N-containing heterocyclo each of which is optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,and dialkylamino, wherein R¹⁰ is attached by a carbon atom when R⁸ andR⁹ together form ═O and r is not 0; R¹¹, R¹² and R¹³ are eachindependently hydrogen, alkyl or phenyl optionally substituted with oneor two substituents independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino; and R¹⁴ isalkyl, monocycloalkyl, bicycloalkyl or unsubstituted tricycloalkyl,optionally substituted heterocyclo, or optionally substituted aryl;provided that when R¹⁴ is alkyl or optionally substituted aryl, then atleast one of R¹¹ or R¹² is other than hydrogen; or R¹¹ is hydrogen, R¹²and R¹³ together form a bridge —CH₂—CH₂— or —CH₂—CH₂—CH₂—, and R¹⁴ ishydrogen, alkyl, monocycloalkyl, bicycloalkyl, unsubstitutedtricycloalkyl, optionally substituted heterocyclo, or optionallysubstituted aryl; or R¹¹ and R¹² are both hydrogen and R¹³ and R¹⁴together with the nitrogen atom to which they are attached form a 4- to7-membered heterocyclic ring; m is 1, 2, or 3; n is 0, 1, 2, or 3; r is0, 1, 2, or 3; and s is 0, 1, or
 2. 2. The compound of claim 1, whereinR³ is selected from the group consisting of methyl, ethyl, iso-pentyl,iso-butyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclopropylmethyl, cyclopropylethyl, methoxymethyl, methoxyethyl,hydroxymethyl, hydroxyethyl, 3-tetrahydrofuranyl,2-tetrahydrofuranylmethyl, 2-tetrahydrofuranylethyl, methylsulfonamidomethyl, methylsulfonamidoethyl, aminocarbonylmethyl, andaminocarbonylethyl.
 3. The compound of claim 2, wherein R³ isiso-propyl.
 4. The compound of claim 1, having the Formula II:

or a pharmaceutically acceptable salt, prodrug or solvate thereof. 5.The compound of claim 1, wherein q is 1 and p is
 2. 6. The compound ofclaim 1, wherein R¹ and R² are each independently selected from thegroup consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, alkoxy,haloalkoxy, nitro, amino, alkylamino, and dialkylamino.
 7. The compoundof claim 6, wherein R¹ and R² are each independently selected from thegroup consisting of hydrogen, methyl, ethyl, fluoro, chloro,trifluoromethyl, difluoromethyl, fluoromethyl, cyano, nitro, methoxy anddifluoromethoxy.
 8. The compound of claim 7, wherein R¹ is hydrogen andR² is trifluoromethyl.
 9. The compound of claim 4, having the FormulaIII:

or a pharmaceutically acceptable salt, prodrug or solvate thereof. 10.The compound of claim 1, wherein Z=Z¹, or a pharmaceutically acceptablesalt, prodrug or solvate thereof.
 11. The compound of claim 10, whereinR⁴ is phenyl which is optionally substituted with 1, 2, or 3substituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, dialkylamino, andhydroxyalkylamino.
 12. The compound of claim 10, wherein R⁴ is selectedfrom the group consisting of pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, pyrrolyl, and pyrazolyl, all of which can beoptionally substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,dialkylamino, and hydroxyalkylamino.
 13. The compound of claim 10,wherein said compound isN-(2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]piperidin-1-yl}ethyl)-4-fluorobenzamideorN-(2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}ethyl)-3,5-bis(trifluoromethyl)phenylbenzamideor a pharmaceutically acceptable salt, prodrug or solvate thereof. 14.The compound of claim 1, wherein Z=Z², or a pharmaceutically acceptablesalt, prodrug or solvate thereof.
 15. The compound of claim 14, whereinR⁷ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, and tert-butyl.
 16. The compound of claim 14, whereinR⁵ is C₁₋₄ alkyl and R⁶ is hydrogen or C₁₋₄ alkyl.
 17. The compound ofclaim 14, wherein R⁷ is selected from the group consisting of methyl,ethyl, propyl, isopropyl, butyl, and tert-butyl, R⁵ is C₁₋₄ alkyl, andR⁶ is hydrogen or C₁₋₄ alkyl.
 18. The compound of claim 14, wherein R⁷is optionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀aryl(C₁₋₄)alkyl, optionally substituted heteroaryl having 5-10 ringatoms, or optionally substituted heteroaryl(C₁₋₄)alkyl having 5-10 ringatoms.
 19. The compound of claim 18, wherein R⁷ is selected from thegroup consisting of phenyl, naphthyl, indenyl, isoindenyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, and pyrazolyl,any of which can be optionally substituted.
 20. The compound of claim19, wherein R⁷ is unsubstituted phenyl or phenyl substituted with 1, 2,or 3 substituents each independently selected from the group consistingof alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, dialkylamino, andhydroxyalkylamino.
 21. The compound of claim 14, wherein said compoundis2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-propionicacid ethyl ester,2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-2-methyl-propionicacid ethyl ester,{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-aceticacid 4-chloro-phenyl ester, or a pharmaceutically acceptable salt,prodrug or solvate thereof.
 22. The compound of claim 1, wherein Z=Z³,or a pharmaceutically acceptable salt, prodrug or solvate thereof. 23.The compound of claim 22, wherein R¹⁰ is selected from the groupconsisting of oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, andthiazolyl, any of which is optionally substituted with one or twosubstituents each independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino.
 24. The compoundof claim 22, wherein R¹⁰ is selected from the group consisting of

wherein R¹⁰¹ is selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino,aminoalkyl, alkylamino, and dialkylamino, and A is O or S.
 25. Thecompound of claim 1, wherein Z=Z⁴, or a pharmaceutically acceptablesalt, prodrug or solvate thereof.
 26. The compound of claim 25, whereinR¹¹, R¹² and R¹³ are each independently hydrogen, alkyl or phenyloptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, haloalkyl,haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino,and dialkylamino; and R¹⁴ is alkyl, monocycloalkyl, bicycloalkyl, orunsubstituted tricycloalkyl, optionally substituted heterocyclo,optionally substituted aryl; provided that when R¹⁴ is alkyl oroptionally substituted aryl, then R¹¹ or R¹² is other than hydrogen. 27.The compound of claim 26, wherein R¹¹, R¹² and R¹³ are each hydrogen andR¹⁴ is monocycloalkyl, bicycloalkyl, or unsubstituted tricycloalkyl oroptionally substituted heterocyclo.
 28. The compound of claim 25,wherein R¹¹ is hydrogen, R¹² and R¹³ together form a bridge —CH₂—CH₂— or—CH₂—CH₂—CH₂—, and R¹⁴ is hydrogen, monocycloalkyl, bicycloalkyl,unsubstituted tricycloalkyl, optionally substituted heterocyclo, oroptionally substituted aryl.
 29. The compound of claim 28, wherein R¹⁴is optionally substituted phenyl.
 30. The compound of claim 25, whereinR¹¹ and R¹² are both hydrogen and R¹³ and R¹⁴ together with the nitrogenatom to which they are attached form a 5- or 6-membered heterocyclicring.
 31. The compound of claim 25, wherein said compound isN-isopropyl-N-[1-(3-oxo-3-piperidin-1-yl-propyl)-piperidin-4-yl]-3-trifluoromethyl-benzene-sulfonamide,N-[1-(2-azepan-1-yl-2-oxo-ethyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide,N-isopropyl-N-[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide,N-(2-chloro-4-fluoro-phenyl)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-isobutyramide,2-{4-[cyclopropyl-(3-trifluoromethyl-benzene-sulfonyl)-amino]-piperidin-1-yl}-N-(4-fluoro-phenyl)-isobutyramide,3-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]-piperidin-1-yl}-N-tert-butyl-butyramide,N-isopropyl-N-[1-(2-oxo-1-phenyl-pyrrolidin-3-yl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide,2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]piperidin-1-yl}-N-phenyl-propionamide,N-cycloheptyl-2-{4-[isopropyl-(3-trifluoromethyl-benzene-sulfonyl)-amino]-piperidin-1-yl}-acetamide,N-bicyclo[2.2.1]hept-2-yl-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide,2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-N-(tetrahydrofuran-3-yl)-acetamide,orN-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide,or a pharmaceutically acceptable salt, prodrug or solvate thereof. 32.The compound of claim 1, wherein Z=Z⁵, or a pharmaceutically acceptablesalt, prodrug or solvate thereof.
 33. The compound of claim 32, whereinZ⁵ is aryl substituted with at least one of alkoxycarbonyl, haloalkyl,carboxy, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl,wherein said aryl can be further optionally substituted.
 34. Thecompound of claim 33, wherein Z⁵ is C₆₋₁₀ aryl substituted with at leastone of alkoxycarbonyl or haloalkyl, wherein said C₆₋₁₀ aryl can befarther optionally substituted.
 35. The compound of claim 34, wherein Z⁵is phenyl substituted with at least one of C₁₋₄ alkoxycarbonyl ortrifluoromethyl.
 36. The compound of claim 35, wherein said phenyl isfurther substituted with a substituent selected from the groupconsisting of halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy,hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino,carboxy, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl.37. The compound of claim 32, wherein Z⁵ is heteroaryl substituted withat least one of alkoxycarbonyl, haloalkyl, carboxy, aminocarbonyl,alkylaminocarbonyl, or dialkylaminocarbonyl, wherein said heteroaryl canbe further optionally substituted.
 38. The compound of claim 37, whereinZ⁵ is heteroaryl having 5-10 ring atoms substituted with at least one ofalkoxycarbonyl or haloalkyl, wherein said heteroaryl can be furtheroptionally substituted.
 39. The compound of claim 38, wherein Z⁵ ispyridyl substituted with at least one of C₁₋₄ alkoxycarbonyl ortrifluoromethyl.
 40. The compound of claim 32, wherein said compound is2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}benzoicacid methyl ester,4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-3′-carboxylicacid ethyl ester,3-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}-5-fluorobenzoicacid ethyl ester,4-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}benzoicacid ethyl ester,N-[1-(3,5-bis-(trifluoromethyl)phenyl)piperidin-1-yl]-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide,or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 41. Apharmaceutical composition, comprising the compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, and apharmaceutically acceptable carrier.
 42. A compound having the Formula Ias claimed in claim 1, wherein the compound is ³H, ¹¹C, or ¹⁴Cradiolabeled, or a pharmaceutically acceptable salt, prodrug or solvatethereof.